{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:28:27Z","timestamp":1791919707008,"version":"4.3.4"},"reference-count":267,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Fund of the Republic of Serbia\u2014RS","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Science Fund of the Republic of Serbia\u2014RS","award":["451-03-68\/2022-14\/200042"],"award-info":[{"award-number":["451-03-68\/2022-14\/200042"]}]},{"name":"Science Fund of the Republic of Serbia\u2014RS","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Ministry of Education, Science and Technological Development RS","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Ministry of Education, Science and Technological Development RS","award":["451-03-68\/2022-14\/200042"],"award-info":[{"award-number":["451-03-68\/2022-14\/200042"]}]},{"name":"Ministry of Education, Science and Technological Development RS","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Science Fund","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Science Fund","award":["451-03-68\/2022-14\/200042"],"award-info":[{"award-number":["451-03-68\/2022-14\/200042"]}]},{"name":"Science Fund","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Singidunum University","award":["6039663"],"award-info":[{"award-number":["6039663"]}]},{"name":"Singidunum University","award":["451-03-68\/2022-14\/200042"],"award-info":[{"award-number":["451-03-68\/2022-14\/200042"]}]},{"name":"Singidunum University","award":["6039663"],"award-info":[{"award-number":["6039663"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Following Alzheimer\u2019s, Parkinson\u2019s disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with \u03b1-synuclein (\u03b1-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, \u03b1-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an \u03b1-helical structure. The central unstructured region of \u03b1-Syn is involved in fibril formation by converting to well-defined, \u03b2-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target \u03b1-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we sum marise the current advances related to \u03b1-Syn aggregation\/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.<\/jats:p>","DOI":"10.3390\/cells11111732","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:04:06Z","timestamp":1653429846000},"page":"1732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":198,"title":["Alpha-Synuclein Aggregation Pathway in Parkinson\u2019s Disease: Current Status and Novel Therapeutic Approaches"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5855-7192","authenticated-orcid":false,"given":"Marija","family":"Vidovi\u0107","sequence":"first","affiliation":[{"name":"Laboratory for Plant Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena G.","family":"Rikalovic","sequence":"additional","affiliation":[{"name":"Environment and Sustainable Development, Singidunum Univeristy, Danijelova 32, 11010 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Giorgetti, S., Greco, C., Tortora, P., and Aprile, F.A. (2018). Targeting amyloid aggregation: An overview of strategies and mechanisms. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201808.0155.v1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14241","DOI":"10.1074\/jbc.RA119.008733","article-title":"Autophagy activation promotes clearance of alpha-synuclein inclusions in fibril-seeded human neural cells","volume":"294","author":"Gao","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108843","DOI":"10.1016\/j.biopha.2019.108843","article-title":"Progress of immunotherapy of anti-\u03b1-synuclein in Parkinson\u2019s disease","volume":"115","author":"Wang","year":"2019","journal-title":"Biomed. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.nbd.2019.01.004","article-title":"Long-term RNAi knockdown of \u03b1-synuclein in the adult rat substantia nigra without neurodegeneration","volume":"125","author":"Zharikov","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_5","unstructured":"Stoker, T.B., and Greenland, J.C. (2018). Parkinson\u2019s disease: Etiology, neuropathology, and pathogenesis. Parkinson\u2019s Disease: Pathogenesis and Clinical Aspects, Exon Publications."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13024-019-0329-1","article-title":"Alpha-synuclein structure and Parkinson\u2019s disease\u2014Lessons and emerging principles","volume":"14","author":"Meade","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional, and national burden of Parkinson\u2019s disease, 1990\u20132016: A systematic analysis for the global burden of disease study","volume":"17","author":"Dorsey","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3389\/fneur.2019.00218","article-title":"Parkinson\u2019s disease and the environment","volume":"10","author":"Ball","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_9","unstructured":"European Parkinson Disease Association (2022, April 09). The European PD Standards of Care Consensus Statement. Available online: https:\/\/www.epda.eu.com\/latest\/resources\/the-european-parkinsons-disease-standards-of-care-consensus-statement\/."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"776847","DOI":"10.3389\/fpubh.2021.776847","article-title":"Global trends in the incidence, prevalence, and years lived with disability of Parkinson\u2019s disease in 204 countries\/territories from 1990 to 2019","volume":"9","author":"Ou","year":"2021","journal-title":"Front. Public Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1212\/WNL.57.3.456","article-title":"Frequency of bowel movements and the future risk of Parkinson\u2019s disease","volume":"57","author":"Abbott","year":"2001","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jns.2009.08.020","article-title":"Gastrointestinal dysfunction in Parkinson\u2019s disease","volume":"289","author":"Jost","year":"2010","journal-title":"J. Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"573696","DOI":"10.3389\/fcell.2020.573696","article-title":"Alpha synuclein connects the gut-brain axis in Parkinson\u2019s disease patients\u2014A view on clinical aspects. Cellular pathology and analytical methodology","volume":"8","author":"Schaeffer","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and treatment of Parkinson\u2019s disease: A review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000511083","article-title":"Alpha-synuclein: The interplay of pathology, neuroinflammation, and environmental factors in Parkinson\u2019s disease","volume":"20","author":"He","year":"2020","journal-title":"Neurodegener. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"702639","DOI":"10.3389\/fnagi.2021.702639","article-title":"Alpha-synuclein as a biomarker of Parkinson\u2019s disease: Good, but not good enough","volume":"13","author":"Ganguly","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41531-020-0117-1","article-title":"Current and projected future economic burden of Parkinson\u2019s disease in the US","volume":"6","author":"Yang","year":"2020","journal-title":"NPJ Parkinsons Dis."},{"key":"ref_19","unstructured":"World Health Organisation, World Federation of Neurology (2017). Atlas. Country Resources for Neurological Disorders, World Health Organisation."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1038\/s41598-021-81185-9","article-title":"Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration","volume":"11","author":"Muddapu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41583-019-0257-7","article-title":"The future of stem cell therapies for Parkinson\u2019s disease","volume":"21","author":"Parmar","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-019-0320-x","article-title":"\u03b1-synuclein in the pathophysiology of Alzheimer\u2019s disease","volume":"14","author":"Twohig","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Br\u00e1s, I.C., and Outeiro, T.F. (2021). Alpha-synuclein: Mechanisms of release and pathology progression in synucleinopathies. Cells, 10.","DOI":"10.3390\/cells10020375"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1124\/pharmrev.120.000133","article-title":"Therapeutics in the pipeline targeting \u03b1-synuclein for Parkinson\u2019s disease","volume":"74","author":"Oh","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation in the alpha-synuclein gene identified in families with Parkinson\u2019s disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1001\/jama.296.6.661","article-title":"Genetic Epidemiology of Parkinson\u2019s Disease (GEO-PD) Consortium. Collaborative analysis of \u03b1-synuclein gene promoter variability and Parkinson\u2019s disease","volume":"296","author":"Maraganore","year":"2006","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nature17939","article-title":"Parkinson-associated risk variant in distal enhancer of \u03b1-synuclein modulates target gene expression","volume":"533","author":"Soldner","year":"2016","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1090278","article-title":"Alpha-synuclein locus triplication causes Parkinson\u2019s disease","volume":"302","author":"Singleton","year":"2003","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0140-6736(04)17103-1","article-title":"Alpha-synuclein locus duplication as a cause of familial Parkinson\u2019s disease","volume":"364","author":"Kachergus","year":"2004","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nm.4269","article-title":"Alpha-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies","volume":"23","author":"Wong","year":"2017","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1002\/mds.27527","article-title":"Genotype-phenotype relations for the Parkinson\u2019s disease genes SNCA, LRRK2, VPS35: MDS Gene systematic review","volume":"3","author":"Trinh","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1073\/pnas.1616152114","article-title":"Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models","volume":"114","author":"Sardi","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","first-page":"2085496","article-title":"Epigenetic and neurological impairments associated with early life exposure to persistent organic pollutants","volume":"2019","author":"Grova","year":"2019","journal-title":"Int. J. Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.1523\/JNEUROSCI.6119-09.2010","article-title":"Methylation regulates alpha-synuclein expression and is decreased in Parkinson\u2019s disease patients\u2019 brains","volume":"30","author":"Jowaed","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S1474-4422(16)30230-7","article-title":"The epidemiology of Parkinson\u2019s disease: Risk factors and prevention","volume":"15","author":"Ascherio","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/jnc.14787","article-title":"Alpha-synuclein at the nexus of genes and environment: The impact of environmental enrichment and stress on brain health and disease","volume":"150","author":"Wassouf","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_38","first-page":"124","article-title":"Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"9","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.envint.2017.04.010","article-title":"Occupational pesticide use and Parkinson\u2019s disease in the Parkinson environment gene (PEG)","volume":"107","author":"Narayan","year":"2017","journal-title":"Study Environ. Int."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ferreira, C., Almeida, C., Tenreiro, S., and Quintas, A. (2020). Neuroprotection or neurotoxicity of illicit drugs on Parkinson\u2019s disease. Life, 10.","DOI":"10.3390\/life10060086"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.biopha.2017.03.100","article-title":"Parkinson\u2019s disease and pesticides: A meta analysis of disease connection and genetic alterations","volume":"90","author":"Ahmed","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101966","DOI":"10.1016\/j.jchemneu.2021.101966","article-title":"Pesticides and Parkinson\u2019s disease: Current and future perspective","volume":"115","author":"Islam","year":"2021","journal-title":"J. Chem. Neuroanat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1074\/jbc.C100560200","article-title":"The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: Paraquat and alpha-synuclein","volume":"277","author":"McCormack","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1006\/exnr.2002.8072","article-title":"Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation","volume":"179","author":"Sherer","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0014-5793(01)02597-2","article-title":"Pesticides directly accelerate the rate of alpha-synuclein fibril formation: A possible factor in Parkinson\u2019s disease","volume":"500","author":"Uversky","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1007\/s13311-013-0211-8","article-title":"Epigenetic landscape of Parkinson\u2019s disease: Emerging role in disease mechanisms and therapeutic modalities","volume":"10","author":"Kaidery","year":"2013","journal-title":"Neurotherapeutics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1289\/ehp.1409313","article-title":"Traffic-related air pollution and Parkinson\u2019s disease in Denmark: A case-control study","volume":"124","author":"Ritz","year":"2016","journal-title":"Environ. Health Perspect."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1177\/0192623307313011","article-title":"Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid \u03b2-42 and \u03b1-synuclein in children and young adults","volume":"36","author":"Solt","year":"2008","journal-title":"Toxicol. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/s41582-021-00531-7","article-title":"Parkinson\u2019s disease and air pollution: Does what we breathe matter?","volume":"17","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.ijheh.2018.12.006","article-title":"Air pollution and Parkinson\u2019s disease: A systematic review and meta-analysis up to 2018","volume":"222","author":"Kasdagli","year":"2019","journal-title":"Int. J. Hyg. Environ. Health."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.2174\/0929867325666171129124616","article-title":"Metals and Parkinson\u2019s disease: Mechanisms and biochemical processes","volume":"25","author":"Bjorklund","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.bbadis.2011.10.002","article-title":"\u03b1-Synuclein misfolding and Parkinson\u2019s disease","volume":"1822","author":"Breydo","year":"2012","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1039\/b926659c","article-title":"Metalloproteomics and metal toxicology of alpha-synuclein","volume":"2","author":"Santner","year":"2010","journal-title":"Metallomics"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Bisaglia, M., and Bubacco, L. (2020). Copper ions and Parkinson\u2019s disease: Why is homeostasis so relevant?. Biomolecules, 10.","DOI":"10.3390\/biom10020195"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1042\/bj3400821","article-title":"Copper (II)-induced self-oligomerization of alpha-synuclein","volume":"340","author":"Paik","year":"1999","journal-title":"Biochem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"616083","DOI":"10.3389\/fgene.2020.616083","article-title":"The function of the metals in regulating epigenetics during Parkinson\u2019s disease","volume":"11","author":"Wei","year":"2021","journal-title":"Front. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1289\/ehp.1002339","article-title":"Association of cumulative lead exposure with Parkinson\u2019s disease","volume":"118","author":"Weisskopf","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1136\/jnnp-2019-322338","article-title":"Parkinson\u2019s disease: Etiopathogenesis and treatment","volume":"91","author":"Jankovic","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nrd.2017.95","article-title":"Zeroing in on neurodegenerative \u03b1-synuclein","volume":"16","author":"Kingwell","year":"2017","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9595","DOI":"10.1074\/jbc.M411805200","article-title":"Structure and dynamics of micelle-bound human \u03b1-synuclein","volume":"280","author":"Ulmer","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12856","DOI":"10.1021\/ja804517m","article-title":"Membrane-bound \u03b1-synuclein forms an extended helix: Long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles","volume":"130","author":"Georgieva","year":"2008","journal-title":"J. Amer. Chem. Soc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13782","DOI":"10.1021\/bi026284c","article-title":"Structural and functional implications of C-terminal regions of alpha-synuclein","volume":"41","author":"Kim","year":"2002","journal-title":"Biochemistry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1093\/bioinformatics\/btx085","article-title":"FELLS: Fast estimator of latent local structure","volume":"33","author":"Piovesan","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1093\/bioinformatics\/btn392","article-title":"HELIQUEST: A web server to screen sequences with specific alpha-helical properties","volume":"24","author":"Gautier","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mirdita, M., Sch\u00fctze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., and Steinegger, M. (2021). ColabFold-Making protein folding accessible to all. bioRxiv.","DOI":"10.1101\/2021.08.15.456425"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6561","DOI":"10.1021\/cr400514h","article-title":"Introducing protein intrinsic disorder","volume":"114","author":"Habchi","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12964-022-00821-7","article-title":"Intrinsically disordered proteins play diverse roles in cell signaling","volume":"20","author":"Bondos","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e2011196118","DOI":"10.1073\/pnas.2011196118","article-title":"Mechanistic basis for receptor-mediated pathological \u03b1-synuclein fibril cell-to-cell transmission in Parkinson\u2019s disease","volume":"118","author":"Zhang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1073\/pnas.0407146102","article-title":"Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein","volume":"102","author":"Bertoncini","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.neuron.2018.09.014","article-title":"Abrogating native \u03b1-synuclein tetramers in mice causes a L-DOPA-responsive motor syndrome closely resembling Parkinson\u2019s disease","volume":"100","author":"Nuber","year":"2018","journal-title":"Neuron"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"U107","DOI":"10.1038\/nature10324","article-title":"Alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation","volume":"477","author":"Bartels","year":"2011","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"17797","DOI":"10.1073\/pnas.1113260108","article-title":"A soluble alpha-synuclein construct forms a dynamic tetramer","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1016\/j.cub.2014.08.027","article-title":"\u03b1-Synuclein multimers cluster synaptic vesicles and attenuate recycling","volume":"24","author":"Wang","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.neuron.2013.09.004","article-title":"The function of alpha-synuclein","volume":"79","author":"Bendor","year":"2013","journal-title":"Neuron"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8465","DOI":"10.1021\/bi0341152","article-title":"Nuclear localization of alpha-synuclein and its interaction with histones","volume":"42","author":"Goers","year":"2003","journal-title":"Biochemistry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0304-3940(02)01258-2","article-title":"Phosphorylation of \u03b1-synuclein characteristic of synucleinopathy lesions is recapitulated in \u03b1-synuclein transgenic Drosophila","volume":"336","author":"Takahashi","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.freeradbiomed.2012.05.024","article-title":"Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: Implications for Parkinson\u2019s disease","volume":"53","author":"Siddiqui","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10571-014-0046-9","article-title":"Alpha-Synuclein is prone to interaction with the GC-box-like sequence in vitro","volume":"34","author":"Ma","year":"2014","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1093\/hmg\/ddy326","article-title":"Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein","volume":"28","author":"Pinho","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.3389\/fnins.2019.01399","article-title":"Alpha-synuclein physiology and pathology: A perspective on cellular structures and organelles","volume":"13","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"a024091","DOI":"10.1101\/cshperspect.a024091","article-title":"Cell biology and pathophysiology of \u03b1-synuclein","volume":"8","author":"Sharma","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1126\/science.1195227","article-title":"Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro","volume":"329","author":"Sharma","year":"2010","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"23","DOI":"10.29245\/2572.942X\/2016\/3.1031","article-title":"Membrane remodelling activity of \u03b1-synuclein","volume":"1","author":"Campioni","year":"2016","journal-title":"J. Neurol. Neuromed."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"11113","DOI":"10.1073\/pnas.1903049116","article-title":"Functional cooperation of alpha-synuclein and VAMP2 in synaptic vesicle recycling","volume":"116","author":"Sun","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1021\/bi4002369","article-title":"Alpha-synuclein can inhibit SNARE-mediated vesicle fusion through direct interactions with lipid bilayers","volume":"52","author":"DeWitt","year":"2013","journal-title":"Biochemistry"},{"key":"ref_86","first-page":"E4274","article-title":"\u03b1-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation","volume":"111","author":"Sharma","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.jmb.2004.02.014","article-title":"Structural determinants of PLD2 inhibition by \u03b1-synuclein","volume":"337","author":"Payton","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fnmol.2019.00299","article-title":"Targeting alpha-synuclein as a therapy for Parkinson\u2019s disease","volume":"12","author":"Fields","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.neulet.2005.01.034","article-title":"\u03b1-synuclein binding to rab3a in multiple system atrophy","volume":"380","author":"Dalfo","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"415","DOI":"10.3389\/fneur.2018.00415","article-title":"Are we ready for detecting \u03b1-synuclein prone to aggregation in patients? The case of \u201cprotein-misfolding cyclic amplification\u201d and \u201creal-time quaking-induced conversion\u201d as diagnostic tools","volume":"9","author":"Paciotti","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/nan.12298","article-title":"Sporadic Parkinson\u2019s disease: Development and distribution of alpha-synuclein pathology","volume":"42","author":"Braak","year":"2016","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_92","first-page":"1","article-title":"Translational inhibition of \u03b1-synuclein by posiphen normalizes distal colon motility in transgenic Parkinson mice","volume":"8","author":"Kuo","year":"2019","journal-title":"Am. J. Neurodegener. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/s41374-019-0195-z","article-title":"Transmission of alpha-synuclein seeds in neurodegenerative disease: Recent developments","volume":"99","author":"Karpowicz","year":"2019","journal-title":"Lab. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.brainres.2015.04.015","article-title":"Alpha-synuclein is associated with the synaptic vesicle apparatus in the human and rat enteric nervous system","volume":"1614","author":"Fricke","year":"2015","journal-title":"Brain Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"575481","DOI":"10.3389\/fnagi.2020.575481","article-title":"Alpha-synuclein accumulation and its phosphorylation in the enteric nervous system of patients without neurodegeneration: An explorative study","volume":"12","author":"Bu","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Martins, M., Rosa, A., Guedes, L.C., Fonseca, B.V., Gotovac, K., Violante, S., Mestre, T., Coelho, M., Rosa, M.M., and Martin, E.R. (2011). Convergence of miRNA expression profiling, alpha-synuclein interacton and GWAS in Parkinson\u2019s disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025443"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/jnc.14808","article-title":"Alpha-synuclein oligomers and fibrils: A spectrum of species, a spectrum of toxicities","volume":"150","author":"Alam","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"699","DOI":"10.3233\/JPD-150642","article-title":"The synaptic function of alpha-synuclein","volume":"5","year":"2015","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","article-title":"Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes","volume":"22","author":"Shahmoradian","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1126\/science.aan6160","article-title":"Structural basis of membrane disruption and cellular toxicity by \u03b1-synuclein oligomers","volume":"358","author":"Fusco","year":"2017","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1038\/s41467-021-24039-2","article-title":"\u03b1-Helical peptidic scaffolds to target \u03b1-synuclein toxic species with nanomolar affinity","volume":"12","author":"Santos","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0014-5793(02)02446-8","article-title":"Accelerated alpha-synuclein fibrillation in crowded milieu","volume":"515","author":"Uversky","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00401-006-0104-6","article-title":"Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers","volume":"112","author":"Beyer","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Schmidt, S., Vogt Waisenhorn, D.M., and Wurs, W. (2022). Chapter 5\u2014\u201cParkinson\u2019s disease\u2014A role of non-enzymatic posttranslational modifications in disease onset and progression?\u201d. Mol. Aspect Med., 101096.","DOI":"10.1016\/j.mam.2022.101096"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ncb748","article-title":"Alpha-Synuclein is phosphorylated in synucleinopathy lesions","volume":"4","author":"Fujiwara","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12035-012-8330-5","article-title":"\u03b1-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration","volume":"47","author":"Beyer","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"5041","DOI":"10.1021\/ja5131726","article-title":"Elucidating the role of site-specific nitration of \u03b1-synuclein in the pathogenesis of Parkinson\u2019s disease via protein semisynthesis and mutagenesis","volume":"137","author":"Burai","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3389\/fnins.2019.00381","article-title":"The roles of post-translational modifications on \u03b1-synuclein in the pathogenesis of Parkinson\u2019s Diseases","volume":"13","author":"Zhang","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41586-019-1808-9","article-title":"Regulation of \u03b1-synuclein by chaperones in mammalian cells","volume":"577","author":"Burmann","year":"2020","journal-title":"Nature"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13176","DOI":"10.1073\/pnas.1704351114","article-title":"SUMOylation and ubiquitination reciprocally regulate \u03b1-synuclein degradation and pathological aggregation","volume":"114","author":"Rott","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1083\/jcb.201010117","article-title":"Sumoylation inhibits alpha-synuclein aggregation and toxicity","volume":"194","author":"Krumova","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1021\/bi501512m","article-title":"Extent of inhibition of \u03b1-synuclein aggregation in vitro by SUMOylation is conjugation site- and SUMO isoform-selective","volume":"54","author":"Abeywardana","year":"2015","journal-title":"Biochemistry"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nchem.2361","article-title":"O-GlcNAc modification blocks the aggregation and toxicity of the protein \u03b1-synuclein associated with Parkinson\u2019s disease","volume":"11","author":"Marotta","year":"2015","journal-title":"Nat. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1042\/BJ20111924","article-title":"Toxic prefibrillar \u03b1-synuclein amyloid oligomers adopt a distinctive antiparallel \u03b2-sheet structure","volume":"443","author":"Celej","year":"2012","journal-title":"Biochem. J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"7873","DOI":"10.1021\/ja075356q","article-title":"Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR","volume":"130","author":"Madine","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.1002\/anie.201309001","article-title":"Sequestration of a beta-hairpin for control of alpha-synuclein aggregation","volume":"53","author":"Mirecka","year":"2014","journal-title":"Angew. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1038\/s41467-020-16386-3","article-title":"Parkinson\u2019s disease associated mutation E46K of \u03b1-synuclein triggers the formation of a distinct fibril structure","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.conb.2020.01.014","article-title":"New insights on the structure of alpha-synuclein fibrils using cryo-electron microscopy","volume":"61","author":"Kovacik","year":"2020","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nsmb.3194","article-title":"Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein","volume":"23","author":"Tuttle","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"e2017452118","DOI":"10.1073\/pnas.2017452118","article-title":"NMR unveils an N-terminal interaction interface on acetylated-\u03b1-synuclein monomers for recruitment to fibrils","volume":"118","author":"Yang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"20305","DOI":"10.1073\/pnas.1922741117","article-title":"Parkinson\u2019s disease-related phosphorylation at Tyr39 rearranges \u03b1-synuclein amyloid fibril structure revealed by cryo-EM","volume":"117","author":"Zhao","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e36402","DOI":"10.7554\/eLife.36402","article-title":"Cryo-EM structure of alpha-synuclein fibrils","volume":"7","author":"Taylor","year":"2018","journal-title":"eLife"},{"key":"ref_123","first-page":"10","article-title":"Cryo-EM of full-length \u03b1-synuclein reveals fibril polymorphs with a common structural kernel","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/s41422-018-0075-x","article-title":"Amyloid fibril structure of \u03b1-synuclein determined by cryo-electron microscopy","volume":"28","author":"Li","year":"2018","journal-title":"Cell Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"13910","DOI":"10.1074\/jbc.RA118.001862","article-title":"The effect of truncation on prion-like properties of \u03b1-synuclein","volume":"293","author":"Terada","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"5132","DOI":"10.1039\/D2CC00212D","article-title":"Rationally designed helical peptidomimetics disrupt alpha-synuclein fibrillation","volume":"58","author":"Bavinton","year":"2022","journal-title":"Chem. Commun."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1126\/science.1063522","article-title":"Kinetic stabilization of the \u03b1-synuclein protofibril by a dopamine-\u03b1-synuclein adduct","volume":"294","author":"Conway","year":"2001","journal-title":"Science"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3233\/JAD-2011-101965","article-title":"Role of advanced glycation on aggregation and DNA binding properties of alpha-synuclein","volume":"24","author":"Padmaraju","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.neuropharm.2013.07.035","article-title":"The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle","volume":"82","author":"Ma","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Santos, J., Pallar\u00e8s, I., and Ventura, S. (2022). Is a cure for Parkinson\u2019s disease hiding inside us?. Trends Biochem. Sci, S0968-0004(22)00025-1.","DOI":"10.1016\/j.tibs.2022.02.001"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1242\/jcs.180737","article-title":"Ca2+ is a key factor in \u03b1-synuclein-induced neurotoxicity","volume":"129","author":"Angelova","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1089\/ars.2015.6343","article-title":"Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson\u2019s disease","volume":"24","author":"Deas","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.nbd.2015.04.007","article-title":"Effects of impaired membrane interactions on \u03b1-synuclein aggregation and neurotoxicity","volume":"79","author":"Ysselstein","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1074\/jbc.M112.418871","article-title":"Monomeric synucleins generate membrane curvature","volume":"288","author":"Westphal","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"e56825","DOI":"10.7554\/eLife.56825","article-title":"\u03b1-synuclein strains that cause distinct pathologies differentially inhibit proteasome","volume":"9","author":"Suzuki","year":"2020","journal-title":"eLife"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"E3138","DOI":"10.1073\/pnas.1301440110","article-title":"Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds","volume":"110","author":"Holmes","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1038\/ncomms2534","article-title":"Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia","volume":"4","author":"Kim","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"9220","DOI":"10.1523\/JNEUROSCI.2617-07.2007","article-title":"Different species of alpha-synuclein oligomers induce calcium influx and seeding","volume":"27","author":"Danzer","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"769506","DOI":"10.3389\/fnagi.2021.769506","article-title":"Alpha-synuclein induced immune cells activation and associated therapy in Parkinson\u2019s disease","volume":"13","author":"Su","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12974-020-01776-7","article-title":"Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson\u2019s disease brain","volume":"17","author":"Rostami","year":"2020","journal-title":"J. Neuroinflam."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"547","DOI":"10.5607\/en.2019.28.5.547","article-title":"Targeting microglial and neuronal Toll-like receptor 2 in synucleinopathies","volume":"28","author":"Kwon","year":"2019","journal-title":"Exp. Neurobiol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s12276-021-00562-6","article-title":"Effects of innate immune receptor stimulation on extracellular \u03b1-synuclein uptake and degradation by brain resident cells","volume":"53","author":"Kim","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1093\/jnen\/nly056","article-title":"Immunohistochemical method and histopathology judging for the systemic synuclein sampling study (S4)","volume":"77","author":"Beach","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1159\/000477990","article-title":"A role for neuronal alpha-synuclein in gastrointestinal immunity","volume":"9","author":"Stolzenberg","year":"2019","journal-title":"J. Innate Immun."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41582-020-0344-4","article-title":"Parkinson disease and the immune system\u2014Associations, mechanisms and therapeutics","volume":"16","author":"Tan","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/s41593-020-0589-7","article-title":"Gut-seeded alpha-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice","volume":"23","author":"Challis","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.neuron.2019.05.035","article-title":"Transneuronal propagation of pathologic \u03b1-synuclein from the gut to the brain models Parkinson\u2019s disease","volume":"103","author":"Kim","year":"2019","journal-title":"Neuron"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/mds.27556","article-title":"Gut-brain axis and the spread of \u03b1-synuclein pathology: Vagal highway or dead end?","volume":"34","author":"Breen","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e13777","DOI":"10.1111\/nmo.13777","article-title":"The gut in Parkinson\u2019s disease: Bottom-up, top-down, or neither?","volume":"32","author":"Neunlist","year":"2020","journal-title":"Neurogestroenerol. Motil."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3389\/fnagi.2021.645996","article-title":"Biomarkers and the role of \u03b1-synuclein in Parkinson\u2019s disease","volume":"13","author":"Du","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/jnc.14809","article-title":"Parkinson\u2019s disease biomarkers based on \u03b1-synuclein","volume":"150","author":"Fayyad","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41436-019-0684-x","article-title":"Genetic testing for Parkinson disease: Current practice, knowledge, and attitudes among US and Canadian movement disorders specialists","volume":"22","author":"Alcalay","year":"2020","journal-title":"Genet. Med."},{"key":"ref_153","unstructured":"Iverson, L. (2013). Enzymes involved in the biosynthesis and degradation of catecholamines. Biochemistry of Biogenic Amines, Springer."},{"key":"ref_154","unstructured":"Stoker, T.B., and Greenland, J.C. (2018). Pharmacological treatment of Parkinson\u2019s disease. Parkinson\u2019s Disease: Pathogenesis and Clinical Aspects, Exon Publications."},{"key":"ref_155","unstructured":"(2022, April 06). Parkinson\u2019s Disease Toolkit. Available online: http:\/\/www.toolkit.parkinson.org\/content\/first-line-meds-and-dosing."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/j.1468-1331.2012.03679.x","article-title":"Levodopa\/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson\u2019s disease","volume":"19","author":"Nyholm","year":"2012","journal-title":"Eur. J. Neurol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1007\/s12325-019-01014-4","article-title":"Current practices for outpatient initiation of levodopa-carbidopa intestinal gel for management of advanced Parkinson\u2019s disease in the United States","volume":"36","author":"Amjad","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Bonam, S.R., Tranchant, C., and Muller, S. (2021). Autophagy-lysosomal pathway as potential therapeutic target in Parkinson\u2019s disease. Cells, 10.","DOI":"10.3390\/cells10123547"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1001\/jamaneurol.2018.4304","article-title":"Utility of neuronal-derived exosomes to examine molecular mechanisms that affect motor function in patients with Parkinson disease","volume":"76","author":"Athauda","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1080\/13543784.2020.1764534","article-title":"Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson\u2019s disease","volume":"29","author":"Glotfelty","year":"2020","journal-title":"Expert Opin. Invest Drugs"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/s41591-019-0507-2","article-title":"Designing stem-cell-based dopamine cell replacement trials for Parkinson\u2019s disease","volume":"25","author":"Barker","year":"2019","journal-title":"Nat. Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/ana.25450","article-title":"Magnetic resonance imaging guided phase 1 trial of putaminal AADC gene therapy for Parkinson\u2019s disease","volume":"85","author":"Christin","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-9007-8_4","article-title":"Derivation of neural stem cells from human parthenogenetic stem cells","volume":"1919","author":"Gonzalez","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/mds.28187","article-title":"Stem cells: Scientific and ethical quandaries of a personalized approach to Parkinson\u2019s disease","volume":"35","author":"Jankovic","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Teil, M., Arotcarena, M.-L., Faggiani, E., Laferriere, F., Bezard, E., and Dehay, B. (2020). Targeting \u03b1-synuclein for PD therapeutics: A pursuit on all fronts. Biomolecules, 10.","DOI":"10.3390\/biom10030391"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Dansithong, W., Paul, S., Scoles, D.R., Pulst, S.M., and Huynh, D.P. (2015). Generation of SNCA cell models using zinc finger nuclease (ZFN) technology for efficient high throughput drug screening. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136930"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1016\/j.ymthe.2018.08.019","article-title":"Downregulation of SNCA expression by targeted editing of DNA methylation: A potential strategy for precision therapy in PD","volume":"26","author":"Kantor","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1126\/science.aaf3934","article-title":"B2-Adrenoreceptor is a regulator of the \u03b1-synuclein gene driving risk of Parkinson\u2019s disease","volume":"357","author":"Mittal","year":"2017","journal-title":"Science"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/mds.108","article-title":"\u03b22- adrenoceptor agonists and antagonists and risk of Parkinson\u2019s disease","volume":"33","author":"Gronich","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1002\/ana.25341","article-title":"B2-adrenoreceptor medications and risk of Parkinson\u2019s disease","volume":"84","author":"Nielsen","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11481-018-09831-0","article-title":"Beta2-adrenoceptor agonists in Parkinson\u2019s disease and other synucleinopathies","volume":"15","author":"Magistrelli","year":"2020","journal-title":"J. Neuroimmune. Pharmacol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.bbrc.2006.01.057","article-title":"Down-regulation of \u03b1-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson\u2019s disease rat model","volume":"341","author":"Yamada","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"12726","DOI":"10.1074\/jbc.M109.086827","article-title":"Post-transcriptional regulation of \u03b1-synuclein expression by mir-7 and mir-153","volume":"285","author":"Doxakis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1172\/JCI64502","article-title":"shRNA targeting \u03b1-synuclein prevents neurodegeneration in a Parkinson\u2019s disease model","volume":"125","author":"Zharikov","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"e241","DOI":"10.1038\/mtna.2015.14","article-title":"Normalization of overexpressed \u03b1-synuclein causing Parkinson\u2019s disease by a moderate gene silencing with RNA interference","volume":"4","author":"Takahashi","year":"2015","journal-title":"Mol. Ther. Nucleic Acids."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.ymthe.2017.11.015","article-title":"Selective \u03b1-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: Potential therapy for Parkinson\u2019s disease","volume":"26","author":"Recasens","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3389\/fphar.2019.00305","article-title":"Antisense oligonucleotide: Basic concepts and therapeutic application in inflammatory bowel disease","volume":"10","author":"Dinallo","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Dhuri, K., Bechtold, C., Quijano, E., Pham, H., Gupta, A., Vikram, A., and Bahal, R. (2020). Antisense oligonucleotides: An emerging area in drug discovery and development. J. Clin. Med., 9.","DOI":"10.3390\/jcm9062004"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"e135633","DOI":"10.1172\/jci.insight.135633","article-title":"\u03b1-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson\u2019s disease","volume":"6","author":"Cole","year":"2021","journal-title":"JCI Insight"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/mt.2010.115","article-title":"In vivo RNAi-mediated alpha-synuclein silencing induces nigrostriatal degeneration","volume":"18","author":"Gorbatyuk","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.brainres.2014.01.010","article-title":"Targeting alpha-synuclein with a microRNA-embedded silencing vector in the rat substantia nigra: Positive and negative effects","volume":"1550","author":"Khodr","year":"2014","journal-title":"Brain Res."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fnmol.2018.00036","article-title":"Silencing alpha-synuclein in mature nigral neurons results in rapid neuroinflammation and subsequent toxicity","volume":"11","author":"Benskey","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-019-0089-y","article-title":"Applications of genome editing technology in the targeted therapy of human diseases: Mechanisms, advances and prospects","volume":"5","author":"Li","year":"2020","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.stem.2013.01.008","article-title":"Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression","volume":"12","author":"Reinhardt","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cbpa.2020.01.001","article-title":"Progress toward the development of the small molecule equivalent of small interfering RNA","volume":"56","author":"Disney","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"7167","DOI":"10.1039\/D0CS00560F","article-title":"Small molecule recognition of disease-relevant RNA structures","volume":"49","author":"Meyer","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13024-017-0218-4","article-title":"Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases","volume":"12","author":"Zhou","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_188","first-page":"142372","article-title":"The anticholinesterase phenserine and its enantiomer posiphen as 5\u2019untranslated-region-directed translation blockers of the Parkinson\u2019s alpha synuclein expression","volume":"2012","author":"Mikkilineni","year":"2012","journal-title":"Parkinsons Dis."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1124\/jpet.106.112102","article-title":"The experimental Alzheimer\u2019s disease drug posiphen [(1)-phenserine] lowers amyloid-\u03b2 peptide levels in cell culture and mice","volume":"320","author":"Lahiri","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"10481","DOI":"10.1073\/pnas.1804198115","article-title":"Small molecule inhibits alpha-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons","volume":"115","author":"Pujols","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/mds.27414","article-title":"Targeted therapies for Parkinson\u2019s disease: From genetics to the clinic","volume":"33","author":"Sardi","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"9375","DOI":"10.1523\/JNEUROSCI.1666-18.2018","article-title":"New frontiers in Parkinson\u2019s disease: From genetics to the clinic","volume":"38","author":"Shihabuddin","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.febslet.2011.03.046","article-title":"Inhibition and disaggregation of alpha-synuclein oligomers by natural polyphenolic compounds","volume":"585","author":"Caruana","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3389\/fnins.2017.00003","article-title":"Metal dyshomeostasis and their pathological role in prion and prion-like diseases: The basis for a nutritional approach","volume":"11","author":"Toni","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"9193","DOI":"10.1074\/jbc.M111.325548","article-title":"Curcumin prevents aggregation in \u03b1-synuclein by increasing reconfiguration rate","volume":"287","author":"Ahmad","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"9862","DOI":"10.1038\/srep09862","article-title":"Curcumin pyrazole and its derivative (N-(3-nitrophenylpyrazole) curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of wild type and mutant \u03b1-synuclein","volume":"5","author":"Ahsan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1093\/hmg\/ddu585","article-title":"(Poly)phenols protect from \u03b1-synuclein toxicity by reducing oxidative stress and promoting autophagy","volume":"24","author":"Macedo","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"955","DOI":"10.4103\/1673-5374.233432","article-title":"Natural polyphenols effects on protein aggregates in Alzheimer\u2019s and Parkinson\u2019s prion-like diseases","volume":"13","author":"Freyssin","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1021\/bi0600749","article-title":"Small molecule inhibitors of \u03b1-synuclein filament assembly","volume":"45","author":"Masuda","year":"2006","journal-title":"Biochemistry"},{"key":"ref_200","first-page":"1282","article-title":"Effects of pharmacological modulators of alpha-synuclein and tau aggregation and internalization","volume":"10","author":"Vasili","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"8206","DOI":"10.1021\/bi900506b","article-title":"Molecular mechanisms underlying the flavonoid-induced inhibition of alpha-synuclein fibrillation","volume":"48","author":"Meng","year":"2009","journal-title":"Biochemistry"},{"key":"ref_202","doi-asserted-by":"crossref","unstructured":"Ono, K., Tsuji, M., Yamasaki, T.R., and Pasinetti, G.M. (2020). Anti-aggregation effects of phenolic compounds on \u03b1-synuclein. Molecules, 25.","DOI":"10.3390\/molecules25102444"},{"key":"ref_203","doi-asserted-by":"crossref","unstructured":"Kazakova, O., Giniyatullina, G., Babkov, D., and Wimmer, Z. (2022). From marine metabolites to the drugs of the future: Squalamine, trodusquemine, their steroid and triterpene analogues. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031075"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"680026","DOI":"10.3389\/fnins.2021.680026","article-title":"Squalamine and its derivatives modulate the aggregation of amyloid-\u03b2 and \u03b1-synuclein and suppress the toxicity of their oligomers","volume":"15","author":"Limbocker","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"E1009","DOI":"10.1073\/pnas.1610586114","article-title":"A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity","volume":"114","author":"Perni","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1021\/acschembio.8b00466","article-title":"Multistep Inhibition of alpha-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine","volume":"13","author":"Perni","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"27582","DOI":"10.1074\/jbc.M114.636027","article-title":"Small molecules detected by second-harmonic generation modulate the conformation of monomeric \u03b1-synuclein and reduce its aggregation in cells","volume":"290","author":"Moree","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/sj.emboj.7600211","article-title":"NMR of alpha-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation","volume":"23","author":"Fernandez","year":"2004","journal-title":"EMBO J."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00401-013-1114-9","article-title":"Anle138b: A novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson\u2019s disease","volume":"125","author":"Wagner","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00401-014-1265-3","article-title":"The oligomer modulator Anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset","volume":"127","author":"Levin","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_211","doi-asserted-by":"crossref","unstructured":"Pujols, J., Pe\u00f1a-D\u00edaz, S., Conde-Gim\u00e9nez, M., Pinheiro, F., Navarro, S., Sancho, J., and Ventura, S. (2017). High-throughput screening methodology to identify alpha-synuclein aggregation inhibitors. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030478"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"101902","DOI":"10.1016\/j.jbc.2022.101902","article-title":"The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple \u03b1-synuclein strains","volume":"298","author":"Pujols","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"11318","DOI":"10.1039\/C6CC04640A","article-title":"Molecular tweezers for lysine and arginine\u2013powerful inhibitors of pathologic protein aggregation","volume":"52","author":"Schrader","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_214","doi-asserted-by":"crossref","unstructured":"Attar, A., Chan, W.T., Klarner, F.G., Schrader, T., and Bitan, G. (2014). Safety and pharmacological characterization of the molecular tweezer CLR01\u2014A broad-spectrum inhibitor of amyloid proteins\u2019 toxicity. BMC Pharm. Toxicol., 15.","DOI":"10.1186\/2050-6511-15-23"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3389\/fchem.2019.00657","article-title":"Molecular lysine tweezers counteract aberrant protein aggregation","volume":"7","author":"Hadrovic","year":"2019","journal-title":"Front. Chem."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s13311-012-0105-1","article-title":"A novel \u201cmolecular tweezer\u201d inhibitor of alpha-synuclein neurotoxicity in vitro and in vivo","volume":"9","author":"Prabhudesai","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.chembiol.2018.08.005","article-title":"Potent alpha-synuclein aggregation inhibitors, identified by high-throughput screening, mainly target the monomeric state","volume":"25","author":"Kurnik","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fnagi.2015.00018","article-title":"Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders","volume":"7","author":"Uversky","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41586-020-2317-6","article-title":"Structures of alpha-synuclein filaments from multiple system atrophy","volume":"585","author":"Schweighauser","year":"2020","journal-title":"Nature"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"e48907","DOI":"10.7554\/eLife.48907","article-title":"Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy","volume":"8","author":"Taylor","year":"2019","journal-title":"eLife"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41586-020-1984-7","article-title":"Discriminating alpha-synuclein strains in Parkinson\u2019s disease and multiple system atrophy","volume":"578","author":"Shahnawaz","year":"2020","journal-title":"Nature"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1021\/acschemneuro.8b00185","article-title":"Peptides, peptidomimetics, and carbohydrate\u2013peptide conjugates as amyloidogenic aggregation inhibitors for Alzheimer\u2019s disease","volume":"9","author":"Ryan","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nchem.1568","article-title":"Inhibition of \u03b1-helix-mediated protein-protein interactions using designed molecules","volume":"5","author":"Azzarito","year":"2013","journal-title":"Nat. Chem."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"5955","DOI":"10.1002\/chem.201204327","article-title":"A designed three-stranded \u03b2-sheet in an \u03b1\/\u03b2 hybrid peptide","volume":"19","author":"Sonti","year":"2013","journal-title":"Chemistry"},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1093\/brain\/aww238","article-title":"A de novo compound targeting \u03b1-synuclein improves deficits in models of Parkinson\u2019s disease","volume":"139","author":"Wrasidlo","year":"2016","journal-title":"Brain"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"16165","DOI":"10.1038\/s41598-018-34490-9","article-title":"The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson\u2019s disease","volume":"8","author":"Price","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_227","first-page":"141","article-title":"NPT088 reduces both amyloid-\u03b2 and tau pathologies in transgenic mice","volume":"2","author":"Levenson","year":"2016","journal-title":"Alzheimers Dement. TRCI"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1034\/j.1399-3011.2002.11002.x","article-title":"Design and characterization of a membrane permeable N-methyl amino acid-containing peptide that inhibits Abeta1-40 fibrillogenesis","volume":"60","author":"Gordon","year":"2002","journal-title":"J. Pept. Res."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"13905","DOI":"10.1074\/jbc.M211976200","article-title":"Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer\u2019s disease","volume":"278","author":"Adessi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_230","unstructured":"Stott, K. (2022, April 14). Peptides Containing N-substituted L-amino Acids for Preventing Beta-Strand Association. Available online: https:\/\/patents.google.com\/patent\/WO2001007473A1\/en."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"354","DOI":"10.2174\/0929866522666150209142649","article-title":"Peptides as modulators of \u03b1-synuclein aggregation","volume":"22","author":"Ruzza","year":"2015","journal-title":"Protein Pept. Lett."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"696440","DOI":"10.3389\/fnins.2021.696440","article-title":"A \u03b2-Wrapin targeting the N-terminus of \u03b1-synuclein monomers reduces fibril-induced aggregation in neurons","volume":"15","author":"Komnig","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nature15368","article-title":"Structure of the toxic core of \u03b1-synuclein from invisible crystals","volume":"525","author":"Rodriguez","year":"2015","journal-title":"Nature"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"e46775","DOI":"10.7554\/eLife.46775","article-title":"Inhibition of synucleinopathic seeding by rationally designed inhibitors","volume":"9","author":"Sangwan","year":"2020","journal-title":"eLife"},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bcp.2017.01.017","article-title":"Potential biomarkers and novel pharmacological targets in protein aggregation-related neurodegenerative diseases","volume":"131","author":"Giacomelli","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.nbd.2018.05.015","article-title":"Lysosome trafficking and signaling in health and neurodegenerative diseases","volume":"122","author":"Lie","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/s41573-019-0036-1","article-title":"Lysosomes as a therapeutic target","volume":"18","author":"Bonam","year":"2019","journal-title":"Nat. Rev. Drug Discove."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1515\/nf-2018-0029","article-title":"Alpha-synuclein as therapeutic target in Parkinson\u2019s disease","volume":"25","year":"2019","journal-title":"Neuroforum"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.neuroscience.2021.01.017","article-title":"The localization of alpha-synuclein in the endocytic pathway","volume":"457","author":"Fakhree","year":"2021","journal-title":"Neuroscience"},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1126\/science.1101738","article-title":"Impaired degradation of mutant \u03b1-synuclein by chaperone-mediated autophagy","volume":"305","author":"Cuervo","year":"2004","journal-title":"Science"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1073\/pnas.1520335113","article-title":"\u03b1-synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models","volume":"113","author":"Mazzulli","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"eaau3112","DOI":"10.1126\/sciadv.aau3112","article-title":"Secondary nucleation and elongation occur at different sites on Alzheimer\u2019s amyloid\u2014Aggregates","volume":"5","author":"Scheidt","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"23727","DOI":"10.1074\/jbc.M503326200","article-title":"The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways","volume":"280","author":"Shin","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"12614","DOI":"10.1021\/bi801475r","article-title":"Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly","volume":"47","author":"Luk","year":"2008","journal-title":"Biochemistry"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1096\/fj.10-164624","article-title":"Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity","volume":"25","author":"Danzer","year":"2011","journal-title":"FASEB J."},{"key":"ref_246","doi-asserted-by":"crossref","unstructured":"Kalia, L.V., Kalia, S.K., Chau, H., Lozano, A.M., Hyman, B.T., and McLean, P.J. (2011). Ubiquitinylation of alpha-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0014695"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"105527","DOI":"10.1016\/j.nbd.2021.105527","article-title":"Molecular chaperones and Parkinson\u2019s disease","volume":"160","author":"Hu","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"25497","DOI":"10.1074\/jbc.M400255200","article-title":"Hsp70 reduces alpha-synuclein aggregation and toxicity","volume":"279","author":"Klucken","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3389\/fnins.2019.01124","article-title":"Different heat shock proteins bind \u03b1-synuclein with distinct mechanisms and synergistically prevent its amyloid aggregation","volume":"13","author":"Jia","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1177\/1756285613493469","article-title":"Targeting heat shock proteins to modulate \u03b1-synuclein toxicity","volume":"7","author":"Jones","year":"2014","journal-title":"Ther. Adv. Neurol. Disor."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1756-6606-2-5","article-title":"Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo","volume":"2","author":"Cullen","year":"2009","journal-title":"Mol. Brain."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.arr.2016.05.004","article-title":"Disorders of lysosomal acidification\u2014The emerging role of v-ATPase in aging and neurodegenerative disease","volume":"32","author":"Colacurcio","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/jnc.14704","article-title":"How is alpha-synuclein cleared from the cell?","volume":"150","author":"Stefanis","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_254","doi-asserted-by":"crossref","unstructured":"Masliah, E., Rockenstein, E., Mante, M., Crews, L., Spencer, B., Adame, A., Patrick, C., Trejo, M., Ubhi, K., and Rohn, T.T. (2011). Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019338"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/mds.26878","article-title":"First-in-human assessment of PRX002, an anti-\u03b1-synuclein monoclonal antibody, in healthy volunteers","volume":"32","author":"Schenk","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"9441","DOI":"10.1523\/JNEUROSCI.5314-13.2014","article-title":"Reducing C-terminal-truncated alphasynuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson\u2019s disease-like models","volume":"34","author":"Games","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.nbd.2018.10.016","article-title":"Development of an aggregate-selective, human-derived \u03b1-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson\u2019s disease models","volume":"124","author":"Weihofen","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"104619","DOI":"10.1016\/j.nbd.2019.104619","article-title":"Optimizing intracellular antibodies (intrabodies\/nanobodies) to treat neurodegenerative disorders","volume":"134","author":"Messer","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jmb.2007.11.096","article-title":"An scFv intrabody against the nonamyloid component of alpha-synuclein reduces intracellular aggregation and toxicity","volume":"377","author":"Lynch","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/pro.3412","article-title":"Exploring the role of post-translational modifications in regulating alpha-synuclein interactions by studying the effects of phosphorylation on nanobody binding","volume":"27","author":"Guilliams","year":"2018","journal-title":"Protein Sci."},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13195-020-00727-x","article-title":"Novel antibodies detect additional \u03b1-synuclein pathology in synucleinopathies: Potential development for immunotherapy","volume":"12","author":"Nimmo","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S1474-4422(20)30136-8","article-title":"Safety and immunogenicity of the \u03b1-synuclein active immunotherapeutic PD01A in patients with Parkinson\u2019s disease: A randomised, single-blinded, phase 1 trial","volume":"19","author":"Volc","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s00401-014-1256-4","article-title":"Next-generation active immunization approach for synucleinopathies: Implications for Parkinson\u2019s disease clinical trials","volume":"127","author":"Mandler","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1523\/JNEUROSCI.1170-17.2017","article-title":"Combined active humoral and cellular immunization approaches for the treatment of synucleinopathies","volume":"38","author":"Rockenstein","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1126\/science.aah3374","article-title":"Pathological \u03b1-synuclein transmission initiated by binding lymphocyte-activation gene 3","volume":"353","author":"Mao","year":"2016","journal-title":"Science"},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1073\/pnas.1700465115","article-title":"GBA1 deficiency negatively affects physiological \u03b1-synuclein tetramers and related multimers","volume":"115","author":"Kim","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_267","unstructured":"Parkinson\u2019s Disease: Challenges, Progress, and Promise (2022, April 09). NIH Publication No.15-5595, Available online: https:\/\/www.ninds.nih.gov\/Disorders\/All-Disorders\/Parkinsons-Disease-Challenges-Progress-and-Promise."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/11\/1732\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:17:53Z","timestamp":1760138273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/11\/1732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":267,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11111732"],"URL":"https:\/\/doi.org\/10.3390\/cells11111732","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,24]]}}}