{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T21:32:13Z","timestamp":1794087133698,"version":"4.8.0"},"reference-count":245,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular \u03b1-synuclein (\u03b1Syn) aggregates known as Lewy bodies (LB). \u03b1Syn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of \u03b1Syn\u2019s role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of \u03b1Syn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic \u03b1Syn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-\u03b2, which may synergistically accelerate disease progression. Targeting \u03b1Syn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin\u2014a myokine implicated in protein clearance and synaptic resilience\u2014underscoring the importance of multimodal strategies in PD management.<\/jats:p>","DOI":"10.3390\/brainsci15121260","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T08:50:20Z","timestamp":1764060620000},"page":"1260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Alpha-Synuclein Neurobiology in Parkinson\u2019s Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6179-2177","authenticated-orcid":false,"given":"Jamir","family":"Pitton Rissardo","sequence":"first","affiliation":[{"name":"Neurology Department, Cooper University Hospital, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2819-6029","authenticated-orcid":false,"given":"Andrew","family":"McGarry","sequence":"additional","affiliation":[{"name":"Neurology Department, Cooper University Hospital, Camden, NJ 08103, USA"},{"name":"Cooper Medical School, Rowan University, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Shi","sequence":"additional","affiliation":[{"name":"Neurology Department, Cooper University Hospital, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8024-2354","authenticated-orcid":false,"given":"Ana Leticia","family":"Fornari Caprara","sequence":"additional","affiliation":[{"name":"Neurology Department, Cooper University Hospital, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George T.","family":"Kannarkat","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Parkinson\u2019s Disease Research, Education and Clinical Center, Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20160065","DOI":"10.1515\/jcim-2016-0065","article-title":"Historical and Cross-Cultural Perspectives on Parkinson\u2019s Disease","volume":"15","author":"Blonder","year":"2018","journal-title":"J. Complement. Integr. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.neurol.2017.08.005","article-title":"Jean-Martin Charcot and Parkinson\u2019s Disease: Teaching and Teaching Materials","volume":"174","author":"Walusinski","year":"2018","journal-title":"Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1080\/0964704X.2019.1622361","article-title":"Centenary of Tretiakoff\u2019s Thesis on the Morphology of Parkinson\u2019s Disease, Evolved on the Grounds of Encephalitis Lethargica Pathology","volume":"28","author":"Holdorff","year":"2019","journal-title":"J. Hist. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.neurol.2021.02.386","article-title":"The Landmark Contributions of Paul Blocq, Georges Marinesco, and \u00c9douard Brissaud in Parkinson\u2019s Disease","volume":"177","author":"Walusinski","year":"2021","journal-title":"Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2012171118","DOI":"10.1073\/pnas.2012171118","article-title":"Structural Insights into \u03b1-Synuclein Monomer-Fibril Interactions","volume":"118","author":"Kumari","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s40478-023-01687-7","article-title":"Neuronal SNCA Transcription during Lewy Body Formation","volume":"11","author":"Kon","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a-Zelayeta, L., Delgado-Minjares, K.M., Villegas-Rojas, M.M., Le\u00f3n-Arcia, K., Santiago-Balmaseda, A., Andrade-Guerrero, J., P\u00e9rez-Segura, I., Ortega-Robles, E., Soto-Rojas, L.O., and Arias-Carri\u00f3n, O. (2025). Redefining Non-Motor Symptoms in Parkinson\u2019s Disease. J. Pers. Med., 15.","DOI":"10.20944\/preprints202503.1395.v1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1002\/mds.22956","article-title":"Who Was the Man Who Discovered the \u201cLewy Bodies\u201d?","volume":"25","author":"Geldsetzer","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1002\/mds.28615","article-title":"Comparison of Locus Coeruleus Pathology with Nigral and Forebrain Pathology in Parkinson\u2019s Disease","volume":"36","author":"Huynh","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3892\/mi.2025.267","article-title":"Let\u00edcia Epidemiology of Autonomic Dysfunction in Parkinson\u2019s Disease (Review)","volume":"5","author":"Rissardo","year":"2025","journal-title":"Med. Int."},{"key":"ref_13","first-page":"517","article-title":"Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for \u03b1-Synuclein in Parkinson\u2019s Disease: The Systemic Synuclein Sampling Study (S4)","volume":"8","author":"Chahine","year":"2018","journal-title":"J. Park. Dis."},{"key":"ref_14","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_15","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_16","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1212\/WNL.56.10.1355","article-title":"Familial Parkinsonism with Synuclein Pathology: Clinical and PET Studies of A30P Mutation Carriers","volume":"56","author":"Kuhn","year":"2001","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"168.e5","DOI":"10.1016\/j.neurobiolaging.2016.10.014","article-title":"SNCA Mutation p.Ala53Glu Is Derived from a Common Founder in the Finnish Population","volume":"50","author":"Pasanen","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1086\/302486","article-title":"Genetic Analysis of Families with Parkinson Disease That Carry the Ala53Thr Mutation in the Gene Encoding Alpha-Synuclein","volume":"65","author":"Athanassiadou","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.febslet.2004.09.038","article-title":"Mutation E46K Increases Phospholipid Binding and Assembly into Filaments of Human Alpha-Synuclein","volume":"576","author":"Choi","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/ana.23894","article-title":"G51D \u03b1-Synuclein Mutation Causes a Novel Parkinsonian-Pyramidal Syndrome","volume":"73","author":"Lesage","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13024-015-0038-3","article-title":"Distinct Clinical and Neuropathological Features of G51D SNCA Mutation Cases Compared with SNCA Duplication and H50Q Mutation","volume":"10","author":"Kiely","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1212\/01.wnl.0000327607.28928.e6","article-title":"Prominent Psychiatric Symptoms and Glucose Hypometabolism in a Family with a SNCA Duplication","volume":"71","author":"Uchiyama","year":"2008","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/ana.10846","article-title":"Comparison of Kindreds with Parkinsonism and Alpha-Synuclein Genomic Multiplications","volume":"55","author":"Farrer","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/ng.487","article-title":"Genome-Wide Association Study Reveals Genetic Risk Underlying Parkinson\u2019s Disease","volume":"41","author":"Schulte","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/jamaneurol.2020.0428","article-title":"Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study","volume":"77","author":"Foo","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1001\/jama.296.6.661","article-title":"Collaborative Analysis of Alpha-Synuclein Gene Promoter Variability and Parkinson Disease","volume":"296","author":"Maraganore","year":"2006","journal-title":"JAMA"},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/mds.27768","article-title":"SNCA Rep1 Promoter Variability Influences Cognition in Parkinson\u2019s Disease","volume":"34","author":"Ng","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_29","first-page":"865","article-title":"Longitudinal Study of SNCA Rep1 Polymorphism on Executive Function in Early Parkinson\u2019s Disease","volume":"12","author":"Tan","year":"2022","journal-title":"J. Park. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1002\/mds.21007","article-title":"Levels of Alpha-Synuclein mRNA in Sporadic Parkinson Disease Patients","volume":"21","author":"Lopez","year":"2006","journal-title":"Mov. Disord."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1002\/mds.27659","article-title":"Parkinson\u2019s Disease Age at Onset Genome-Wide Association Study: Defining Heritability, Genetic Loci, and \u03b1-Synuclein Mechanisms","volume":"34","author":"Blauwendraat","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e70167","DOI":"10.1111\/ene.70167","article-title":"Cerebrospinal Fluid Phosphorylated Alpha-Synuclein in Newly Diagnosed Parkinson\u2019s Disease","volume":"32","author":"Pedersen","year":"2025","journal-title":"Eur. J. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/35081564","article-title":"Alpha-Synuclein and Neurodegenerative Diseases","volume":"2","author":"Goedert","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","article-title":"Synuclein: A Neuron-Specific Protein Localized to the Nucleus and Presynaptic Nerve Terminal","volume":"8","author":"Maroteaux","year":"1988","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mehra, S., Gadhe, L., Bera, R., Sawner, A.S., and Maji, S.K. (2021). Structural and Functional Insights into \u03b1-Synuclein Fibril Polymorphism. Biomolecules, 11.","DOI":"10.3390\/biom11101419"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/pro.2088","article-title":"N-Terminal Acetylation of \u03b1-Synuclein Induces Increased Transient Helical Propensity and Decreased Aggregation Rates in the Intrinsically Disordered Monomer","volume":"21","author":"Kang","year":"2012","journal-title":"Protein Sci."},{"key":"ref_38","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":"7","author":"Marotta","year":"2015","journal-title":"Nat. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1021\/acschembio.7b00113","article-title":"O-GlcNAcylation of \u03b1-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding","volume":"12","author":"Lewis","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1073\/pnas.1808845116","article-title":"\u03b1-Synuclein O-GlcNAcylation Alters Aggregation and Toxicity, Revealing Certain Residues as Potential Inhibitors of Parkinson\u2019s Disease","volume":"116","author":"Levine","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"319","DOI":"10.4103\/1673-5374.244795","article-title":"Implications of Alpha-Synuclein Nitration at Tyrosine 39 in Methamphetamine-Induced Neurotoxicity In Vitro and In Vivo","volume":"14","author":"Qiao","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0006-8993(02)02498-8","article-title":"Tyrosine 125 of Alpha-Synuclein Plays a Critical Role for Dimerization Following Nitrative Stress","volume":"938","author":"Takahashi","year":"2002","journal-title":"Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"27230","DOI":"10.1074\/jbc.M212436200","article-title":"Effects of Oxidative and Nitrative Challenges on Alpha-Synuclein Fibrillogenesis Involve Distinct Mechanisms of Protein Modifications","volume":"278","author":"Norris","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"47746","DOI":"10.1074\/jbc.M408906200","article-title":"Functional Consequences of Alpha-Synuclein Tyrosine Nitration: Diminished Binding to Lipid Vesicles and Increased Fibril Formation","volume":"279","author":"Hodara","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1172\/JCI85456","article-title":"Activation of Tyrosine Kinase C-Abl Contributes to \u03b1-Synuclein-Induced Neurodegeneration","volume":"126","author":"Brahmachari","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1523\/JNEUROSCI.5922-09.2010","article-title":"Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits Alpha-Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions","volume":"30","author":"Paleologou","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"E3945","DOI":"10.1073\/pnas.1309991110","article-title":"Polo-like Kinase 2 Regulates Selective Autophagic \u03b1-Synuclein Clearance and Suppresses Its Toxicity In Vivo","volume":"110","author":"Oueslati","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1096\/fj.01-0517fje","article-title":"Multiple Phosphorylation of Alpha-Synuclein by Protein Tyrosine Kinase Syk Prevents Eosin-Induced Aggregation","volume":"16","author":"Negro","year":"2002","journal-title":"FASEB J."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"16233","DOI":"10.1021\/bi048453u","article-title":"Impact of the Acidic C-Terminal Region Comprising Amino Acids 109-140 on Alpha-Synuclein Aggregation In Vitro","volume":"43","author":"Hoyer","year":"2004","journal-title":"Biochemistry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.1073\/pnas.97.9.4897","article-title":"Fiber Diffraction of Synthetic Alpha-Synuclein Filaments Shows Amyloid-like Cross-Beta Conformation","volume":"97","author":"Serpell","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","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_55","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1021\/ja300094r","article-title":"Semisynthetic, Site-Specific Ubiquitin Modification of \u03b1-Synuclein Reveals Differential Effects on Aggregation","volume":"134","author":"Meier","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1074\/jbc.M704809200","article-title":"Monoubiquitylation of Alpha-Synuclein by Seven in Absentia Homolog (SIAH) Promotes Its Aggregation in Dopaminergic Cells","volume":"283","author":"Rott","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000112832","article-title":"Red Blood Cells Are the Major Source of Alpha-Synuclein in Blood","volume":"5","author":"Barbour","year":"2008","journal-title":"Neurodegener. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1146\/annurev-pathol-031920-092547","article-title":"The Membrane Interactions of Synuclein: Physiology and Pathology","volume":"16","author":"Runwal","year":"2021","journal-title":"Annu. Rev. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Brembati, V., Faustini, G., Longhena, F., and Bellucci, A. (2023). Alpha Synuclein Post Translational Modifications: Potential Targets for Parkinson\u2019s Disease Therapy?. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1197853"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Iyer, A., Sidhu, A., and Subramaniam, V. (2022). How Important Is the N-Terminal Acetylation of Alpha-Synuclein for Its Function and Aggregation into Amyloids?. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1003997"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1080\/17576180.2024.2407718","article-title":"An Immunoassay for the Quantification of Phosphorylated \u03b1-Synuclein at Serine 129 in Human Cerebrospinal Fluid","volume":"16","author":"Silva","year":"2024","journal-title":"Bioanalysis"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41531-023-00444-w","article-title":"Dynamic Physiological \u03b1-Synuclein S129 Phosphorylation Is Driven by Neuronal Activity","volume":"9","author":"Ramalingam","year":"2023","journal-title":"NPJ Park. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.1016\/j.neuron.2023.11.020","article-title":"Serine-129 Phosphorylation of \u03b1-Synuclein Is an Activity-Dependent Trigger for Physiologic Protein-Protein Interactions and Synaptic Function","volume":"111","author":"Madhivanan","year":"2023","journal-title":"Neuron"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"732879","DOI":"10.5402\/2011\/732879","article-title":"Serine 129 Phosphorylation of \u03b1-Synuclein Cross-Links with Tissue Transglutaminase to Form Lewy Body-Like Inclusion Bodies","volume":"2011","author":"Bi","year":"2011","journal-title":"ISRN Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5512","DOI":"10.1038\/s41467-022-33252-6","article-title":"Small Soluble \u03b1-Synuclein Aggregates Are the Toxic Species in Parkinson\u2019s Disease","volume":"13","author":"Emin","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature10324","article-title":"\u03b1-Synuclein Occurs Physiologically as a Helically Folded Tetramer That Resists Aggregation","volume":"477","author":"Bartels","year":"2011","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e202300282","DOI":"10.1002\/tcr.202300282","article-title":"Navigating \u03b1-Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets","volume":"24","author":"Galkin","year":"2024","journal-title":"Chem. Rec."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41422-024-01022-2","article-title":"\u03b1-Synuclein Amyloid Fibril Directly Binds to LC3B and Suppresses SQSTM1\/P62-Mediated Selective Autophagy","volume":"35","author":"Xu","year":"2025","journal-title":"Cell Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"102017","DOI":"10.1016\/j.arr.2023.102017","article-title":"A Comprehensive Review of Protein Misfolding Disorders, Underlying Mechanism, Clinical Diagnosis, and Therapeutic Strategies","volume":"90","author":"Basha","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Musteikyt\u0117, G., Jayaram, A.K., Xu, C.K., Vendruscolo, M., Krainer, G., and Knowles, T.P.J. (2021). Interactions of \u03b1-Synuclein Oligomers with Lipid Membranes. Biochim. Biophys. Acta Biomembr., 1863.","DOI":"10.1016\/j.bbamem.2020.183536"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1038\/s44321-024-00083-5","article-title":"Aggregation-Resistant Alpha-Synuclein Tetramers Are Reduced in the Blood of Parkinson\u2019s Patients","volume":"16","author":"Wallis","year":"2024","journal-title":"EMBO Mol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/j.bbapap.2015.08.009","article-title":"Small-Angle Neutron Scattering Reveals the Assembly of Alpha-Synuclein in Lipid Membranes","volume":"1854","author":"Anunciado","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/jnc.14806","article-title":"Cellular Models of Alpha-Synuclein Toxicity and Aggregation","volume":"150","author":"Delenclos","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41531-022-00388-7","article-title":"Revisiting the Specificity and Ability of Phospho-S129 Antibodies to Capture Alpha-Synuclein Biochemical and Pathological Diversity","volume":"8","author":"Lashuel","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/ana.27288","article-title":"Blood \u03b1-Synuclein Separates Parkinson\u2019s Disease from Dementia with Lewy Bodies","volume":"98","author":"Kannarkat","year":"2025","journal-title":"Ann. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/ana.26166","article-title":"Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and \u03b1-Synuclein Mutations","volume":"90","author":"Jo","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Suzuki, M., Sango, K., and Nagai, Y. (2022). Roles of \u03b1-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031519"},{"key":"ref_78","first-page":"1077","article-title":"The AAV-\u03b1-Synuclein Model of Parkinson\u2019s Disease: An Update","volume":"14","author":"Mattsson","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.nbd.2004.07.001","article-title":"Alpha-Synuclein and Transgenic Mouse Models","volume":"17","author":"Fernagut","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.neurobiolaging.2021.01.010","article-title":"Age-Related Increase of Alpha-Synuclein Oligomers Is Associated with Motor Disturbances in L61 Transgenic Mice","volume":"101","author":"Roshanbin","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Paumier, K.L., Sukoff Rizzo, S.J., Berger, Z., Chen, Y., Gonzales, C., Kaftan, E., Li, L., Lotarski, S., Monaghan, M., and Shen, W. (2013). Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson\u2019s Disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070274"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e00915","DOI":"10.1002\/brb3.915","article-title":"Early Fine Motor Impairment and Behavioral Dysfunction in (Thy-1)-h[A30P] Alpha-Synuclein Mice","volume":"8","author":"Gumucio","year":"2018","journal-title":"Brain Behav."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Amschl, D., Neddens, J., Havas, D., Flunkert, S., Rabl, R., R\u00f6mer, H., Rockenstein, E., Masliah, E., Windisch, M., and Hutter-Paier, B. (2013). Time Course and Progression of Wild Type \u03b1-Synuclein Accumulation in a Transgenic Mouse Model. BMC Neurosci., 14.","DOI":"10.1186\/1471-2202-14-6"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"103418","DOI":"10.1016\/j.mcn.2019.103418","article-title":"Overexpression of Human wtTDP-43 Causes Impairment in Hippocampal Plasticity and Behavioral Deficits in CAMKII-tTa Transgenic Mouse Model","volume":"102","author":"Quadri","year":"2020","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"35104","DOI":"10.1074\/jbc.M111.247965","article-title":"E46K Human Alpha-Synuclein Transgenic Mice Develop Lewy-like and Tau Pathology Associated with Age-Dependent, Detrimental Motor Impairment","volume":"286","author":"Emmer","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/2051-5960-2-29","article-title":"Alpha-Synuclein Spreading in M83 Mice Brain Revealed by Detection of Pathological \u03b1-Synuclein by Enhanced ELISA","volume":"2","author":"Brot","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e2628","DOI":"10.1002\/brb3.2628","article-title":"Modeling Parkinson\u2019s Disease-Related Symptoms in Alpha-Synuclein Overexpressing Mice","volume":"12","author":"Aniszewska","year":"2022","journal-title":"Brain Behav."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Benito, M., Granado, N., Garc\u00eda-Sanz, P., Michel, A., Dumoulin, M., and Moratalla, R. (2020). Modeling Parkinson\u2019s Disease with the Alpha-Synuclein Protein. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00356"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.bbi.2022.01.007","article-title":"Neurodegeneration by \u03b1-Synuclein-Specific T Cells in AAV-A53T-\u03b1-Synuclein Parkinson\u2019s Disease Mice","volume":"101","author":"Karikari","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_90","first-page":"1555","article-title":"A Summary of Phenotypes Observed in the In Vivo Rodent Alpha-Synuclein Preformed Fibril Model","volume":"11","author":"Polinski","year":"2021","journal-title":"J. Park. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"159753","DOI":"10.1016\/j.scitotenv.2022.159753","article-title":"Manganese-Induced \u03b1-Synuclein Overexpression Promotes the Accumulation of Dysfunctional Synaptic Vesicles and Hippocampal Synaptotoxicity by Suppressing Rab26-Dependent Autophagy in Presynaptic Neurons","volume":"858","author":"Ma","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Yoo, G., Shin, Y.-K., and Lee, N.K. (2023). The Role of \u03b1-Synuclein in SNARE-Mediated Synaptic Vesicle Fusion. J. Mol. Biol., 435.","DOI":"10.1016\/j.jmb.2022.167775"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1038\/s41556-024-01456-1","article-title":"VAMP2 Chaperones \u03b1-Synuclein in Synaptic Vesicle Co-Condensates","volume":"26","author":"Wang","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Stephens, A.D., Villegas, A.F., Chung, C.W., Vanderpoorten, O., Pinotsi, D., Mela, I., Ward, E., McCoy, T.M., Cubitt, R., and Routh, A.F. (2023). \u03b1-Synuclein Fibril and Synaptic Vesicle Interactions Lead to Vesicle Destruction and Increased Lipid-Associated Fibril Uptake into iPSC-Derived Neurons. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-04884-1"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Risiglione, P., Zinghirino, F., Di Rosa, M.C., Magr\u00ec, A., and Messina, A. (2021). Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson\u2019s Disease: The Emerging Role of VDAC. Biomolecules, 11.","DOI":"10.3390\/biom11050718"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.neuron.2017.11.036","article-title":"\u03b1-Synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton","volume":"97","author":"Ordonez","year":"2018","journal-title":"Neuron"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/s41419-023-06251-8","article-title":"Aggregation of Alpha-Synuclein Disrupts Mitochondrial Metabolism and Induce Mitophagy via Cardiolipin Externalization","volume":"14","author":"Lurette","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/s41593-022-01140-3","article-title":"Pathological Structural Conversion of \u03b1-Synuclein at the Mitochondria Induces Neuronal Toxicity","volume":"25","author":"Choi","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"578047","DOI":"10.1016\/j.jneuroim.2023.578047","article-title":"A Functional Role for Alpha-Synuclein in Neuroimmune Responses","volume":"376","author":"Heiden","year":"2023","journal-title":"J. Neuroimmunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1016\/j.cell.2021.09.007","article-title":"Microglia Jointly Degrade Fibrillar Alpha-Synuclein Cargo by Distribution through Tunneling Nanotubes","volume":"184","author":"Scheiblich","year":"2021","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.4103\/NRR.NRR-D-24-01129","article-title":"Role of Tunneling Nanotubes in Neuroglia","volume":"21","author":"Xu","year":"2026","journal-title":"Neural Regen. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"6237","DOI":"10.1038\/s41467-021-26519-x","article-title":"Microglia-Specific Overexpression of \u03b1-Synuclein Leads to Severe Dopaminergic Neurodegeneration by Phagocytic Exhaustion and Oxidative Toxicity","volume":"12","author":"Bido","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Bisi, N., Feni, L., Peqini, K., P\u00e9rez-Pe\u00f1a, H., Ongeri, S., Pieraccini, S., and Pellegrino, S. (2021). \u03b1-Synuclein: An All-Inclusive Trip Around Its Structure, Influencing Factors and Applied Techniques. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.666585"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41531-022-00313-y","article-title":"Lipid Level Alteration in Human and Cellular Models of Alpha Synuclein Mutations","volume":"8","author":"Avisar","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41531-022-00423-7","article-title":"Protein Aggregation and Calcium Dysregulation Are Hallmarks of Familial Parkinson\u2019s Disease in Midbrain Dopaminergic Neurons","volume":"8","author":"Virdi","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41401-024-01359-9","article-title":"The Correlation between Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Ca(2+) Transport in the Pathogenesis of Diseases","volume":"46","author":"Zhao","year":"2025","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1016\/j.neurobiolaging.2013.06.006","article-title":"Deregulation of Calcium Homeostasis Mediates Secreted \u03b1-Synuclein-Induced Neurotoxicity","volume":"34","author":"Melachroinou","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1750-1326-5-56","article-title":"ER Stress Response Plays an Important Role in Aggregation of \u03b1-Synuclein","volume":"5","author":"Jiang","year":"2010","journal-title":"Mol. Neurodegener."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1126\/science.1129462","article-title":"Alpha-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson\u2019s Models","volume":"313","author":"Cooper","year":"2006","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"25009","DOI":"10.1074\/jbc.M300227200","article-title":"Alpha-Synuclein Is Degraded by Both Autophagy and the Proteasome","volume":"278","author":"Webb","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/s41419-021-04138-0","article-title":"Alpha-Synuclein Defects Autophagy by Impairing SNAP29-Mediated Autophagosome-Lysosome Fusion","volume":"12","author":"Tang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"30009","DOI":"10.1074\/jbc.M501308200","article-title":"Alpha-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability","volume":"280","author":"Chen","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e13522","DOI":"10.1111\/acel.13522","article-title":"\u03b1-Synuclein Suppresses Microglial Autophagy and Promotes Neurodegeneration in a Mouse Model of Parkinson\u2019s Disease","volume":"20","author":"Tu","year":"2021","journal-title":"Aging Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"7585","DOI":"10.1523\/JNEUROSCI.5809-11.2012","article-title":"Disrupted Autophagy Leads to Dopaminergic Axon and Dendrite Degeneration and Promotes Presynaptic Accumulation of \u03b1-Synuclein and LRRK2 in the Brain","volume":"32","author":"Friedman","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1038\/s41467-020-15119-w","article-title":"Microglia Clear Neuron-Released \u03b1-Synuclein via Selective Autophagy and Prevent Neurodegeneration","volume":"11","author":"Choi","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1038\/ncomms2534","article-title":"Neuron-Released Oligomeric \u03b1-Synuclein Is an Endogenous Agonist of TLR2 for Paracrine Activation of Microglia","volume":"4","author":"Kim","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/glia.22437","article-title":"Toll-like Receptor 4 Is Required for \u03b1-Synuclein Dependent Activation of Microglia and Astroglia","volume":"61","author":"Fellner","year":"2013","journal-title":"Glia"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Moda, F., Ciullini, A., Dellarole, I.L., Lombardo, A., Campanella, N., Bufano, G., Cazzaniga, F.A., and Giaccone, G. (2023). Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception. Front. Biosci., 28.","DOI":"10.31083\/j.fbl2810255"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-Propagation of Pathogenic Protein Aggregates in Neurodegenerative Diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s40478-014-0176-9","article-title":"Models of \u03b1-Synuclein Aggregation in Parkinson\u2019s Disease","volume":"2","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1227157","article-title":"Pathological \u03b1-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice","volume":"338","author":"Luk","year":"2012","journal-title":"Science"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1084\/jem.20160833","article-title":"Unique Pathological Tau Conformers from Alzheimer\u2019s Brains Transmit Tau Pathology in Nontransgenic Mice","volume":"213","author":"Guo","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6892","DOI":"10.1038\/s41467-023-42705-5","article-title":"\u03b1-Synuclein Aggregates Amplified from Patient-Derived Lewy Bodies Recapitulate Lewy Body Diseases in Mice","volume":"14","author":"Uemura","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13024-020-00368-6","article-title":"Initiation and Propagation of \u03b1-Synuclein Aggregation in the Nervous System","volume":"15","author":"Hijaz","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Graves, N.J., Gambin, Y., and Sierecki, E. (2023). \u03b1-Synuclein Strains and Their Relevance to Parkinson\u2019s Disease, Multiple System Atrophy, and Dementia with Lewy Bodies. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512134"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nm1752","article-title":"Dopamine Neurons Implanted into People with Parkinson\u2019s Disease Survive without Pathology for 14 Years","volume":"14","author":"Mendez","year":"2008","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"6544","DOI":"10.1073\/pnas.1605245113","article-title":"Extensive Graft-Derived Dopaminergic Innervation Is Maintained 24 Years after Transplantation in the Degenerating Parkinsonian Brain","volume":"113","author":"Li","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.celrep.2014.05.033","article-title":"A-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded \u03b1-Synuclein and Neurodegeneration","volume":"7","author":"Tran","year":"2014","journal-title":"Cell Rep."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuron.2011.08.033","article-title":"Exogenous \u03b1-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death","volume":"72","author":"Luk","year":"2011","journal-title":"Neuron"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1016\/j.neurobiolaging.2011.06.022","article-title":"Prion-like Acceleration of a Synucleinopathy in a Transgenic Mouse Model","volume":"33","author":"Mougenot","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1093\/brain\/awz296","article-title":"Intrastriatal Alpha-Synuclein Fibrils in Monkeys: Spreading, Imaging and Neuropathological Changes","volume":"142","author":"Chu","year":"2019","journal-title":"Brain"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.52586\/5010","article-title":"Seed Amplification Assays for Diagnosing Synucleinopathies: The Issue of Influencing Factors","volume":"26","author":"Bellomo","year":"2021","journal-title":"Front. Biosci."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1093\/clinchem\/hvad111","article-title":"Early and Accurate Diagnosis of Parkinson Disease May Be Rooted in Seed Amplification Assays","volume":"69","author":"Tropea","year":"2023","journal-title":"Clin. Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s13311-022-01332-6","article-title":"Overexpression-Induced \u03b1-Synuclein Brain Spreading","volume":"20","author":"Harbachova","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s00401-024-02781-3","article-title":"Current Insights and Assumptions on \u03b1-Synuclein in Lewy Body Disease","volume":"148","author":"Leak","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1162\/netn_a_00208","article-title":"Braiding Braak and Braak: Staging Patterns and Model Selection in Network Neurodegeneration","volume":"5","author":"Putra","year":"2021","journal-title":"Netw. Neurosci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.reth.2023.12.019","article-title":"Host-to-Graft Propagation of Inoculated \u03b1-Synuclein into Transplanted Human Induced Pluripotent Stem Cell-Derived Midbrain Dopaminergic Neurons","volume":"25","author":"Gima","year":"2024","journal-title":"Regen. Ther."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1080\/17434440.2021.1969913","article-title":"Noninvasive Vagus Nerve Stimulation in Parkinson\u2019s Disease: Current Status and Future Prospects","volume":"18","author":"Sigurdsson","year":"2021","journal-title":"Expert Rev. Med. Devices"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00441-022-03665-2","article-title":"Prion Strains: Shining New Light on Old Concepts","volume":"392","author":"Block","year":"2023","journal-title":"Cell Tissue Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1002\/mds.28628","article-title":"Recent Advances in the Development of Stem-Cell-Derived Dopaminergic Neuronal Transplant Therapies for Parkinson\u2019s Disease","volume":"36","author":"Barbuti","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s40478-022-01440-6","article-title":"Discrepancy between Distribution of Alpha-Synuclein Oligomers and Lewy-Related Pathology in Parkinson\u2019s Disease","volume":"10","author":"Sekiya","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s00401-010-0664-3","article-title":"Multi-Organ Distribution of Phosphorylated Alpha-Synuclein Histopathology in Subjects with Lewy Body Disorders","volume":"119","author":"Beach","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.nbd.2017.07.018","article-title":"Distinct \u03b1-Synuclein Strains and Implications for Heterogeneity among \u03b1-Synucleinopathies","volume":"109","author":"Peng","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41586-020-1984-7","article-title":"Discriminating \u03b1-Synuclein Strains in Parkinson\u2019s Disease and Multiple System Atrophy","volume":"578","author":"Shahnawaz","year":"2020","journal-title":"Nature"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41586-020-2317-6","article-title":"Structures of \u03b1-Synuclein Filaments from Multiple System Atrophy","volume":"585","author":"Schweighauser","year":"2020","journal-title":"Nature"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1038\/s41467-024-46832-5","article-title":"Structure of Alpha-Synuclein Fibrils Derived from Human Lewy Body Dementia Tissue","volume":"15","author":"Dhavale","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41593-019-0541-x","article-title":"\u03b1-Synuclein Strains Target Distinct Brain Regions and Cell Types","volume":"23","author":"Lau","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.neuron.2023.03.021","article-title":"Cognitive Heterogeneity in Parkinson\u2019s Disease: A Mechanistic View","volume":"111","author":"Weintraub","year":"2023","journal-title":"Neuron"},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Bridi, J.C., and Hirth, F. (2018). Mechanisms of \u03b1-Synuclein Induced Synaptopathy in Parkinson\u2019s Disease. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00080"},{"key":"ref_150","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_151","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1016\/j.neuron.2024.08.003","article-title":"Gut-Induced Alpha-Synuclein and Tau Propagation Initiate Parkinson\u2019s and Alzheimer\u2019s Disease Co-Pathology and Behavior Impairments","volume":"112","author":"Xiang","year":"2024","journal-title":"Neuron"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40035-022-00318-w","article-title":"Intestine-Derived \u03b1-Synuclein Initiates and Aggravates Pathogenesis of Parkinson\u2019s Disease in Drosophila","volume":"11","author":"Liu","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41593-024-01866-2","article-title":"Propagation of Pathologic \u03b1-Synuclein from Kidney to Brain May Contribute to Parkinson\u2019s Disease","volume":"28","author":"Yuan","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"105440","DOI":"10.1016\/j.parkreldis.2023.105440","article-title":"Single-Dose Intranasal Administration of \u03b1-Syn PFFs Induce Lewy Neurite-like Pathology in Olfactory Bulbs","volume":"112","author":"Sawamura","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/med.22091","article-title":"\u03b1-Synuclein in Parkinson\u2019s Disease: From Bench to Bedside","volume":"45","author":"Bellini","year":"2024","journal-title":"Med. Res. Rev."},{"key":"ref_156","first-page":"6838965","article-title":"A Case of Parkinson\u2019s Disease with No Lewy Body Pathology Due to a Homozygous Exon Deletion in Parkin","volume":"2018","author":"Johansen","year":"2018","journal-title":"Case Rep. Neurol. Med."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s40478-018-0617-y","article-title":"Isolated Nigral Degeneration without Pathological Protein Aggregation in Autopsied Brains with LRRK2 p.R1441H Homozygous and Heterozygous Mutations","volume":"6","author":"Takanashi","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/ana.20321","article-title":"Alpha-Synuclein Pathology Does Not Predict Extrapyramidal Symptoms or Dementia","volume":"57","author":"Parkkinen","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Chahine, L.M., Lafontant, D.-E., Ho Choi, S., Iwaki, H., Blauwendraat, C., Singleton, A.B., Brumm, M.C., Alcalay, R.N., Merchant, K., and Nudelman, K.N.H. (2024). LRRK2-Associated Parkinsonism with and Without In Vivo Evidence of Alpha-Synuclein Aggregates. medRxiv, medRxiv 2024.07.22.24310806.","DOI":"10.1101\/2024.07.22.24310806"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41570-021-00254-9","article-title":"Quantifying Misfolded Protein Oligomers as Drug Targets and Biomarkers in Alzheimer and Parkinson Diseases","volume":"5","author":"Kulenkampff","year":"2021","journal-title":"Nat. Rev. Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"127","DOI":"10.14802\/jmd.24075","article-title":"\u03b1-Synuclein: A Promising Biomarker for Parkinson\u2019s Disease and Related Disorders","volume":"17","author":"Hatano","year":"2024","journal-title":"J. Mov. Disord."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/s41596-022-00787-3","article-title":"Seed Amplification Assay for the Detection of Pathologic Alpha-Synuclein Aggregates in Cerebrospinal Fluid","volume":"18","author":"Pritzkow","year":"2023","journal-title":"Nat. Protoc."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1038\/s41591-023-02358-9","article-title":"Propagative \u03b1-Synuclein Seeds as Serum Biomarkers for Synucleinopathies","volume":"29","author":"Okuzumi","year":"2023","journal-title":"Nat. Med."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Rissardo, J.P., and Fornari Caprara, A.L. (2025). Alpha-Synuclein Seed Amplification Assays in Parkinson\u2019s Disease: A Systematic Review and Network Meta-Analysis. Clin. Pract., 15.","DOI":"10.3390\/clinpract15060107"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1097\/OPX.0000000000002168","article-title":"Tear \u03b1-Synuclein as a Biomarker for Parkinson\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"101","author":"Akowuah","year":"2024","journal-title":"Optom. Vis. Sci."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s10286-018-0581-4","article-title":"Skin Nerve \u03b1-Synuclein Deposits in Parkinson\u2019s Disease and Other Synucleinopathies: A Review","volume":"29","author":"Donadio","year":"2019","journal-title":"Clin. Auton. Res."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Burger, D., Fenyi, A., Bousset, L., Stahlberg, H., and Melki, R. (2021). Cryo-EM Structure of Alpha-Synuclein Fibrils Amplified by PMCA from PD and MSA Patient Brains. bioRxiv, bioRxiv 2021.07.08.451588.","DOI":"10.1101\/2021.07.08.451588"},{"key":"ref_168","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_169","doi-asserted-by":"crossref","first-page":"RP92775","DOI":"10.7554\/eLife.92775.3","article-title":"Brain-Derived and in Vitro-Seeded Alpha-Synuclein Fibrils Exhibit Distinct Biophysical Profiles","volume":"13","author":"Lee","year":"2024","journal-title":"Elife"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1021\/acs.jcim.6b00721","article-title":"Characterization of Biomolecular Helices and Their Complementarity Using Geometric Analysis","volume":"57","author":"Hauser","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/s41586-022-05319-3","article-title":"Structures of \u03b1-Synuclein Filaments from Human Brains with Lewy Pathology","volume":"610","author":"Yang","year":"2022","journal-title":"Nature"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00401-023-02550-8","article-title":"New SNCA Mutation and Structures of \u03b1-Synuclein Filaments from Juvenile-Onset Synucleinopathy","volume":"145","author":"Yang","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s40478-019-0840-1","article-title":"Luminescent Conjugated Oligothiophenes Distinguish between \u03b1-Synuclein Assemblies of Parkinson\u2019s Disease and Multiple System Atrophy","volume":"7","author":"Klingstedt","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1038\/s41467-019-13564-w","article-title":"Structural Heterogeneity of \u03b1-Synuclein Fibrils Amplified from Patient Brain Extracts","volume":"10","author":"Jung","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Frieg, B., Geraets, J.A., Stroh\u00e4ker, T., Dienemann, C., Mavroeidi, P., Jung, B.C., Kim, W.S., Lee, S.-J., Xilouri, M., and Zweckstetter, M. (2022). Quaternary Structure of Patient-Homogenate Amplified \u03b1-Synuclein Fibrils Modulates Seeding of Endogenous \u03b1-Synuclein. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03948-y"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","article-title":"Assessment of Heterogeneity among Participants in the Parkinson\u2019s Progression Markers Initiative Cohort Using \u03b1-Synuclein Seed Amplification: A Cross-Sectional Study","volume":"22","author":"Siderowf","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1002\/mds.29162","article-title":"\u03b1-Synuclein V15A Variant in Familial Parkinson\u2019s Disease Exhibits a Weaker Lipid-Binding Property","volume":"37","author":"Daida","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"e4693","DOI":"10.1002\/pro.4693","article-title":"Parkinson\u2019s Disease-Linked V15A Mutation Facilitates \u03b1-Synuclein Aggregation by Reducing Membrane Affinity","volume":"32","author":"Buratti","year":"2023","journal-title":"Protein Sci."},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Sengupta, U., and Kayed, R. (2022). Amyloid \u03b2, Tau, and \u03b1-Synuclein Aggregates in the Pathogenesis, Prognosis, and Therapeutics for Neurodegenerative Diseases. Prog. Neurobiol., 214.","DOI":"10.1016\/j.pneurobio.2022.102270"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1749-6632.2009.05118.x","article-title":"The Progression of Pathology in Parkinson\u2019s Disease","volume":"1184","author":"Halliday","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Rissardo, J.P., and Caprara, A.L. (2025). A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies. Clin. Pract., 15.","DOI":"10.3390\/clinpract15030065"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1093\/brain\/awt192","article-title":"Disease Duration and the Integrity of the Nigrostriatal System in Parkinson\u2019s Disease","volume":"136","author":"Kordower","year":"2013","journal-title":"Brain"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1093\/brain\/awad388","article-title":"Nigrostriatal Tau Pathology in Parkinsonism and Parkinson\u2019s Disease","volume":"147","author":"Chu","year":"2024","journal-title":"Brain"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","article-title":"Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1212\/01.wnl.0000240220.33950.0c","article-title":"Parkinsonism, Lrrk2 G2019S, and Tau Neuropathology","volume":"67","author":"Rajput","year":"2006","journal-title":"Neurology"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.parkreldis.2012.03.024","article-title":"LRRK2 I2020T Mutation Is Associated with Tau Pathology","volume":"18","author":"Ujiie","year":"2012","journal-title":"Park. Relat. Disord."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1212\/WNL.0000000000002744","article-title":"Absence of Lewy Pathology Associated with PINK1 Homozygous Mutation","volume":"86","author":"Takanashi","year":"2016","journal-title":"Neurology"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"4621","DOI":"10.1093\/hmg\/ddu178","article-title":"Parkinson\u2019s Disease-Linked Mutations in VPS35 Induce Dopaminergic Neurodegeneration","volume":"23","author":"Tsika","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.nbd.2015.02.031","article-title":"Progressive Dopaminergic Alterations and Mitochondrial Abnormalities in LRRK2 G2019S Knock-in Mice","volume":"78","author":"Yue","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1212\/WNL.0b013e318278fe32","article-title":"Lewy Pathology Is Not the First Sign of Degeneration in Vulnerable Neurons in Parkinson Disease","volume":"79","author":"Milber","year":"2012","journal-title":"Neurology"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/alz.12318","article-title":"A Novel Tau-Based Rhesus Monkey Model of Alzheimer\u2019s Pathogenesis","volume":"17","author":"Beckman","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref_192","unstructured":"Webster, J., Stone, W., Yang, Y.-T., Miller, A., Childers, G., Corbin-Stein, N., Mudium, N., Molina, J., Won, W.-J., and Sandoval, I. (2024). Amyloid-Beta, Alpha-Synuclein and Tau Aggregated Co-Pathologies Enhance Neuropathology and Neuroinflammation. bioRxiv."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1523\/JNEUROSCI.0490-10.2010","article-title":"Synergistic Interactions between Abeta, Tau, and Alpha-Synuclein: Acceleration of Neuropathology and Cognitive Decline","volume":"30","author":"Clinton","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_194","first-page":"444","article-title":"The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders","volume":"8","author":"Irwin","year":"2018","journal-title":"J. Alzheimers Dis. Park."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-981-32-9358-8_14","article-title":"Relationship Between Tau, \u03b2 Amyloid and \u03b1-Synuclein Pathologies","volume":"1184","author":"Walker","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1136\/jnnp-2016-313775","article-title":"Concomitant AD Pathology Affects Clinical Manifestation and Survival in Dementia with Lewy Bodies","volume":"88","author":"Lemstra","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Collins, L.M., and Williams-Gray, C.H. (2016). The Genetic Basis of Cognitive Impairment and Dementia in Parkinson\u2019s Disease. Front. Psychiatry, 7.","DOI":"10.3389\/fpsyt.2016.00089"},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Yoo, S.-J., Son, G., Bae, J., Kim, S.Y., Yoo, Y.K., Park, D., Baek, S.Y., Chang, K.-A., Suh, Y.-H., and Lee, Y.-B. (2020). Longitudinal Profiling of Oligomeric A\u03b2 in Human Nasal Discharge Reflecting Cognitive Decline in Probable Alzheimer\u2019s Disease. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-68148-2"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"e22493","DOI":"10.1096\/fj.202200235R","article-title":"Interactions of Amyloid Coaggregates with Biomolecules and Its Relevance to Neurodegeneration","volume":"36","author":"Murakami","year":"2022","journal-title":"FASEB J."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1136\/jnnp-2021-327788","article-title":"Differential Levels of Plasma Biomarkers of Neurodegeneration in Lewy Body Dementia, Alzheimer\u2019s Disease, Frontotemporal Dementia and Progressive Supranuclear Palsy","volume":"93","author":"Chouliaras","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High Performance Plasma Amyloid-\u03b2 Biomarkers for Alzheimer\u2019s Disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"100003","DOI":"10.1016\/j.tjpad.2024.100003","article-title":"Plasma Amyloid-\u03b2 Precursor Protein (669\u2013711)\/Amyloid-\u03b2 (1\u201342) Ratio Is Associated with Cognition in Alzheimer\u2019s Disease","volume":"12","author":"Sakashita","year":"2025","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1111\/j.1471-4159.2012.07847.x","article-title":"Cross-Seeding Effects of Amyloid \u03b2-Protein and \u03b1-Synuclein","volume":"122","author":"Ono","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00401-022-02421-8","article-title":"APOE4 Exacerbates \u03b1-Synuclein Seeding Activity and Contributes to Neurotoxicity in Alzheimer\u2019s Disease with Lewy Body Pathology","volume":"143","author":"Jin","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"25","DOI":"10.14283\/jpad.2022.84","article-title":"Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer\u2019s and Parkinson\u2019s Patients","volume":"10","author":"Fang","year":"2023","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"107257","DOI":"10.1016\/j.parkreldis.2024.107257","article-title":"A Phase 2b, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Intravenous Prasinezumab in Early-Stage Parkinson\u2019s Disease (PADOVA): Rationale, Design, and Baseline Data","volume":"132","author":"Nikolcheva","year":"2024","journal-title":"Park. Relat. Disord."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41531-025-00886-4","article-title":"Prasinezumab Slows Motor Progression in Parkinsons Disease: Beyond the Clinical Data","volume":"11","author":"Xiao","year":"2025","journal-title":"NPJ Park. Dis."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1038\/s41591-024-03101-8","article-title":"Target Engagement and Immunogenicity of an Active Immunotherapeutic Targeting Pathological \u03b1-Synuclein: A Phase 1 Placebo-Controlled Trial","volume":"30","author":"Eijsvogel","year":"2024","journal-title":"Nat. Med."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1212\/WNL.0000000000202579","article-title":"Reducing \u03b1-Synuclein in Human CSF.; an Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEDI1341, an \u03b1-Synuclein-Specific Antibody, in Healthy Volunteers and Parkinson\u2019s Disease Patients (P1\u201311.007)","volume":"100","author":"Shering","year":"2023","journal-title":"Neurology"},{"key":"ref_210","unstructured":"Carson, S. (2025, January 1\u20135). Results from ORCHESTRA, A Phase II Proof-of-Concept Study Assessing the Efficacy and Safety of Minzasolmin in People with Early-Stage Parkinson\u2019s Disease. Proceedings of the AD\/PD 2025, Vienna, Austria."},{"key":"ref_211","first-page":"1234","article-title":"Neuropathology of Dementia in Patients with Parkinson\u2019s Disease: A Systematic Review of Autopsy Studies","volume":"90","author":"Smith","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1093\/brain\/awac171","article-title":"Tau Accelerates \u03b1-Synuclein Aggregation and Spreading in Parkinson\u2019s Disease","volume":"145","author":"Pan","year":"2022","journal-title":"Brain"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40478-023-01534-9","article-title":"Different MAPT Haplotypes Influence Expression of Total MAPT in Postmortem Brain Tissue","volume":"11","author":"Tauber","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1056\/NEJMoa2202867","article-title":"Trial of Prasinezumab in Early-Stage Parkinson\u2019s Disease","volume":"387","author":"Pagano","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/psp4.12538","article-title":"Phase II Dose Selection for Alpha Synuclein-Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain","volume":"9","author":"Kuchimanchi","year":"2020","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_216","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."},{"key":"ref_217","unstructured":"Young, A., Kim, K., Cifrese, J., Hatami, A., Nguyen, H., Yu, Q., Marlen, K., Paschon, D., Ledeboer, A., and Lam, S. (2024). SNCA Gene Repression Mediated by Zinc Finger Repressors (ZFRs) as a Therapeutic Approach for Parkinson\u2019s Disease, Cell Press."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41531-023-00453-9","article-title":"Irisin Exhibits Neuroprotection by Preventing Mitochondrial Damage in Parkinson\u2019s Disease","volume":"9","author":"Zhang","year":"2023","journal-title":"NPJ Park. Dis."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"e2204835119","DOI":"10.1073\/pnas.2204835119","article-title":"Amelioration of Pathologic \u03b1-Synuclein-Induced Parkinson\u2019s Disease by Irisin","volume":"119","author":"Kam","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1515\/revneuro-2020-0099","article-title":"Physical Exercise Promotes Brain Remodeling by Regulating Epigenetics, Neuroplasticity and Neurotrophins","volume":"32","author":"Liang","year":"2021","journal-title":"Rev. Neurosci."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1152\/japplphysiol.00343.2011","article-title":"Exercise Training Increases Mitochondrial Biogenesis in the Brain","volume":"111","author":"Steiner","year":"2011","journal-title":"J. Appl. Physiol."},{"key":"ref_222","doi-asserted-by":"crossref","unstructured":"Wang, S., Zhou, Y., Wu, Y., Lang, Y., Mao, Y., Pan, G., and Gao, Z. (2024). Long-Term Aerobic Exercise Improves Learning Memory Capacity and Effects on Oxidative Stress Levels and Keap1\/Nrf2\/GPX4 Pathway in the Hippocampus of APP\/PS1 Mice. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1505650"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1093\/jnen\/nlz106","article-title":"Regular Aerobic Exercise-Alleviated Dysregulation of CAMKII\u03b1 Carbonylation to Mitigate Parkinsonism via Homeostasis of Apoptosis with Autophagy","volume":"79","author":"Liu","year":"2020","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"E404","DOI":"10.1152\/ajpendo.00391.2017","article-title":"Parkin Is Required for Exercise-Induced Mitophagy in Muscle: Impact of Aging","volume":"315","author":"Chen","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_225","doi-asserted-by":"crossref","unstructured":"Tyler, J., Podaras, M., Richardson, B., Roeder, N., Hammond, N., Hamilton, J., Blum, K., Gold, M., Baron, D.A., and Thanos, P.K. (2023). High Intensity Interval Training Exercise Increases Dopamine D2 Levels and Modulates Brain Dopamine Signaling. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1257629"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13024-022-00560-w","article-title":"LRP1 Is a Neuronal Receptor for \u03b1-Synuclein Uptake and Spread","volume":"17","author":"Chen","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_227","doi-asserted-by":"crossref","unstructured":"Vanderperre, B., Muraleedharan, A., Dorion, M.-F., Larroquette, F., Del Cid Pellitero, E., Rajakulendran, N., Chen, C.X.-Q., Larivi\u00e8re, R., Michaud-Tardif, C., and Goiran, T. (2025). Novel Regulators of Heparan Sulfate Proteoglycans Modulate Cellular Uptake of \u03b1-Synuclein Fibrils. Commun. Biol., 8.","DOI":"10.1038\/s42003-025-08786-2"},{"key":"ref_228","doi-asserted-by":"crossref","unstructured":"Deyell, J.S., Sriparna, M., Ying, M., and Mao, X. (2023). The Interplay between \u03b1-Synuclein and Microglia in \u03b1-Synucleinopathies. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032477"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"8968","DOI":"10.1073\/pnas.132197599","article-title":"Human Alpha-Synuclein-Harboring Familial Parkinson\u2019s Disease-Linked Ala-53 \u2192 Thr Mutation Causes Neurodegenerative Disease with Alpha-Synuclein Aggregation in Transgenic Mice","volume":"99","author":"Lee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"aah3374","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_231","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-P\u00e9rez, A., Granda-D\u00edaz, R., Aguilar-Garc\u00eda, C., Sordo-Bahamonde, C., and Gonzalez, S. (2024). Deciphering LAG-3: Unveiling Molecular Mechanisms and Clinical Advancements. Biomark. Res., 12.","DOI":"10.1186\/s40364-024-00671-0"},{"key":"ref_232","doi-asserted-by":"crossref","unstructured":"Feller, B., Fallon, A., Luo, W., Nguyen, P.T., Shlaifer, I., Lee, A.K., Chofflet, N., Yi, N., Khaled, H., and Karkout, S. (2023). \u03b1-Synuclein Preformed Fibrils Bind to \u03b2-Neurexins and Impair \u03b2-Neurexin-Mediated Presynaptic Organization. Cells, 12.","DOI":"10.1101\/2023.01.28.526024"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"e23017","DOI":"10.1096\/fj.202201605RR","article-title":"Sortilin Acts as an Endocytic Receptor for \u03b1-Synuclein Fibril","volume":"37","author":"Ishiyama","year":"2023","journal-title":"FASEB J."},{"key":"ref_234","doi-asserted-by":"crossref","unstructured":"Kumar, M., Singh, K., Joshi, J., Sharma, S., Kumar, A., Irungbam, K., Mahawar, M., and Saini, M. (2025). Mechanistic Insights into Alpha-Synuclein Binding to P2RX7: A Molecular Dynamic and Docking Study. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0319098"},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"6750","DOI":"10.1038\/s41467-023-42305-3","article-title":"The \u03b1-Synuclein PET Tracer [18F] ACI-12589 Distinguishes Multiple System Atrophy from Other Neurodegenerative Diseases","volume":"14","author":"Smith","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1016\/j.neuron.2024.05.006","article-title":"Imaging \u03b1-Synuclein Pathologies in Animal Models and Patients with Parkinson\u2019s and Related Diseases","volume":"112","author":"Endo","year":"2024","journal-title":"Neuron"},{"key":"ref_237","doi-asserted-by":"crossref","unstructured":"Marek, K. (2025, October 23). Assessment of [18F] C05-05 PET Imaging in Participants with Parkinson\u2019s Disease in the PPMI Study (PPMI C05-05 PET Imaging). Available online: https:\/\/www.protocols.io\/view\/assessment-of-18f-c05-05-pet-imaging-in-participan-eq2lyw3ymvx9\/v1.","DOI":"10.17504\/protocols.io.eq2lyw3ymvx9\/v1"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1007\/s00259-020-05133-x","article-title":"[(11)C]MODAG-001-towards a PET Tracer Targeting \u03b1-Synuclein Aggregates","volume":"48","author":"Kuebler","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1039\/D5MD00057B","article-title":"The Development of a PET Radiotracer for Imaging Alpha Synuclein Aggregates in Parkinson\u2019s Disease","volume":"16","author":"Tian","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_240","doi-asserted-by":"crossref","unstructured":"Zhang, J., Jin, J., Su, D., Feng, T., and Zhao, H. (2023). Tau-PET Imaging in Parkinson\u2019s Disease: A Systematic Review and Meta-Analysis. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1145939"},{"key":"ref_241","unstructured":"Prakash, N., Date, M., Marek, K., Date, M., Chowdhury, S., and Deputy, C. (2025, October 23). PROTOCOL SIGNATURE PAGE Version 2.0 Dated 12 June 2025 NX PI-2160 in PD. Available online: https:\/\/www.ppmi-info.org\/sites\/default\/files\/docs\/029Protocol_NXPI2620PD_12June2025_Final.pdf."},{"key":"ref_242","doi-asserted-by":"crossref","unstructured":"Capotosti, F. (2025). A-Synuclein PET Imaging: From Clinical Utility in Multiple System Atrophy to the Possible Diagnosis of Parkinson\u2019s Disease. Cells, 14.","DOI":"10.3390\/cells14110834"},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-024-00787-9","article-title":"Positron Emission Tomography Tracers for Synucleinopathies","volume":"20","author":"Xiang","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"24774","DOI":"10.1021\/acsomega.4c01301","article-title":"Advancing Parkinson\u2019s Disease Diagnostics: The Potential of Arylpyrazolethiazole Derivatives for Imaging \u03b1-Synuclein Aggregates","volume":"9","author":"Bonanno","year":"2024","journal-title":"ACS Omega"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s11682-019-00097-5","article-title":"Altered Functional Connectivity of Dentate Nucleus in Parkinsonian and Cerebellar Variants of Multiple System Atrophy","volume":"13","author":"Yang","year":"2019","journal-title":"Brain Imaging Behav."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/12\/1260\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T09:24:35Z","timestamp":1764062675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/12\/1260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":245,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["brainsci15121260"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15121260","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}