{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T06:52:53Z","timestamp":1787899973024,"version":"build-2784847793"},"reference-count":130,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T00:00:00Z","timestamp":1642636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R322-2019-2544"],"award-info":[{"award-number":["R322-2019-2544"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010809","name":"Jascha Fonden","doi-asserted-by":"publisher","award":["3650"],"award-info":[{"award-number":["3650"]}],"id":[{"id":"10.13039\/100010809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008445","name":"Parkinsonforeningen","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008445","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alpha-synucleinopathies include Parkinson\u2019s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (\u03b1syn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic \u03b1syn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different \u03b1syn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic \u03b1syn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic \u03b1syn from peripheral organs to the brain.<\/jats:p>","DOI":"10.3390\/biom12020168","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T22:40:20Z","timestamp":1642718420000},"page":"168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Passive Immunization in Alpha-Synuclein Preclinical Animal Models"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0940-3098","authenticated-orcid":false,"given":"Jonas","family":"Folke","sequence":"first","affiliation":[{"name":"Department of Geriatric Medicine, University Hospital Essen, 45147 Essen, Germany"},{"name":"Research Laboratory for Stereology and Neuroscience, Department of Neurology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, 2400 Copenhagen, Denmark"},{"name":"Copenhagen Center for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, 2400 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-9097","authenticated-orcid":false,"given":"Nelson","family":"Ferreira","sequence":"additional","affiliation":[{"name":"DANDRITE-Danish Research Institute of Translational Neuroscience, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-1817","authenticated-orcid":false,"given":"Tomasz","family":"Brudek","sequence":"additional","affiliation":[{"name":"Research Laboratory for Stereology and Neuroscience, Department of Neurology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, 2400 Copenhagen, Denmark"},{"name":"Copenhagen Center for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, 2400 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Borghammer","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9384-1279","authenticated-orcid":false,"given":"Nathalie","family":"Van Den Berge","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,20]]},"reference":[{"key":"ref_1","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_2","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_3","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_4","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_5","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40035-019-0172-x","article-title":"Beyond the synucleinopathies: Alpha synuclein as a driving force in neurodegenerative comorbidities","volume":"8","author":"Visanji","year":"2019","journal-title":"Transl. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0022-510X(89)90219-0","article-title":"Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome)","volume":"94","author":"Papp","year":"1989","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00401-010-0672-3","article-title":"Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: An update","volume":"119","author":"Jellinger","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kovacs, G.G. (2016). Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020189"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1212\/WNL.0000000000009433","article-title":"Dementia with Lewy bodies and Parkinson disease dementia: More different than similar?","volume":"94","author":"Armstrong","year":"2020","journal-title":"Neurology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/mds.27138","article-title":"How does parkinson\u2019s disease begin? Perspectives on neuroanatomical pathways, prions, and histology","volume":"33","author":"Borghammer","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fneur.2019.00363","article-title":"Autonomic Dysfunction in \u03b1-Synucleinopathies","volume":"10","author":"Illigens","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11910-016-0673-2","article-title":"Pure Autonomic Failure","volume":"16","author":"Thaisetthawatkul","year":"2016","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.autneu.2017.10.007","article-title":"Diagnosis of multiple system atrophy","volume":"211","author":"Palma","year":"2018","journal-title":"Auton. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3233\/JPD-202481","article-title":"The \u03b1-Synuclein Origin and Connectome Model (SOC Model) of Parkinson\u2019s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline","volume":"11","author":"Borghammer","year":"2021","journal-title":"J. Parkinsons. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105557","DOI":"10.1016\/j.nbd.2021.105557","article-title":"Neuropathological evidence of body-first vs. brain-first Lewy body disease","volume":"161","author":"Borghammer","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.3389\/fimmu.2019.02033","article-title":"Encoding the Sequence of Specific Autoantibodies Against beta-Amyloid and alpha-Synuclein in Neurodegenerative Diseases","volume":"10","author":"Albus","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9441","DOI":"10.1523\/JNEUROSCI.5314-13.2014","article-title":"Reducing C-terminal-truncated \u03b1-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson\u2019s disease-like models","volume":"34","author":"Games","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_19","first-page":"16","article-title":"Development of Passive Immunotherapies for Synucleinopathies","volume":"31","author":"Kallunki","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1080\/13543784.2020.1771693","article-title":"Immunization therapies for Parkinson\u2019s disease: State of the art and considerations for future clinical trials","volume":"29","author":"Antonini","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00401-019-01974-5","article-title":"Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology","volume":"137","author":"Li","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"815","DOI":"10.3389\/fneur.2018.00815","article-title":"A Systematic Review and Meta-Analysis of Alpha Synuclein Auto-Antibodies in Parkinson\u2019s Disease","volume":"9","author":"Scott","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13024-017-0187-7","article-title":"Autoimmune antibody decline in Parkinson\u2019s disease and Multiple System Atrophy; a step towards immunotherapeutic strategies","volume":"12","author":"Brudek","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.3389\/fimmu.2019.02253","article-title":"Distinct Autoimmune Anti-\u03b1-Synuclein Antibody Patterns in Multiple System Atrophy and Parkinson\u2019s Disease","volume":"10","author":"Folke","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.parkreldis.2021.05.001","article-title":"Cerebrospinal fluid and plasma distribution of anti-\u03b1-synuclein IgMs and IgGs in multiple system atrophy and Parkinson\u2019s disease","volume":"87","author":"Folke","year":"2021","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00441-018-2854-6","article-title":"Is Lewy pathology in the human nervous system chiefly an indicator of neuronal protection or of toxicity?","volume":"373","author":"Chartier","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"408","DOI":"10.3389\/fnins.2016.00408","article-title":"Alpha-Synuclein Oligomers-Neurotoxic Molecules in Parkinson\u2019s Disease and Other Lewy Body Disorders","volume":"10","author":"Ingelsson","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_28","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_29","first-page":"reviews3002","article-title":"The synucleins","volume":"3","author":"George","year":"2002","journal-title":"Genome Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"a009399","DOI":"10.1101\/cshperspect.a009399","article-title":"\u03b1-Synuclein in Parkinson\u2019s disease","volume":"2","author":"Stefanis","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9364","DOI":"10.1523\/JNEUROSCI.4787-13.2014","article-title":"Synucleins regulate the kinetics of synaptic vesicle endocytosis","volume":"34","author":"Vargas","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nn.4529","article-title":"\u03b1-Synuclein promotes dilation of the exocytotic fusion pore","volume":"20","author":"Logan","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_33","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_34","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_35","doi-asserted-by":"crossref","first-page":"17797","DOI":"10.1073\/pnas.1113260108","article-title":"A soluble \u03b1-synuclein construct forms a dynamic tetramer","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6755","DOI":"10.1038\/s41598-018-25133-0","article-title":"Structural characteristics and membrane interactions of tandem \u03b1-synuclein oligomers","volume":"8","author":"Dong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/pro.2056","article-title":"N-Terminal acetylation is critical for forming \u03b1-helical oligomer of \u03b1-synuclein","volume":"21","author":"Trexler","year":"2012","journal-title":"Protein Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21110","DOI":"10.1074\/jbc.M116.726612","article-title":"The Impact of N-terminal Acetylation of \u03b1-Synuclein on Phospholipid Membrane Binding and Fibril Structure","volume":"291","author":"Iyer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5702","DOI":"10.1039\/C5CP04549E","article-title":"Conformational ensemble of human \u03b1-synuclein physiological form predicted by molecular simulations","volume":"18","author":"Rossetti","year":"2016","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1074\/jbc.M008919200","article-title":"A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly","volume":"276","author":"Giasson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neulet.2013.04.058","article-title":"\u03b1-Synuclein mutations cluster around a putative protein loop","volume":"546","author":"Kara","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"L\u00e1zaro, D.F., Rodrigues, E.F., Langohr, R., Shahpasandzadeh, H., Ribeiro, T., Guerreiro, P., Gerhardt, E., Kr\u00f6hnert, K., Klucken, J., and Pereira, M.D. (2014). Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004741"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00401-017-1755-1","article-title":"Alpha-synuclein oligomers: A new hope","volume":"134","author":"Roberts","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.bbadis.2008.07.006","article-title":"A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders","volume":"1792","author":"Jellinger","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00441-004-0956-9","article-title":"Stages in the development of Parkinson\u2019s disease-related pathology","volume":"318","author":"Braak","year":"2004","journal-title":"Cell Tissue Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1365-2990.2007.00874.x","article-title":"Parkinson\u2019s disease: A dual-hit hypothesis","volume":"33","author":"Hawkes","year":"2007","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00401-008-0345-7","article-title":"Evidence that incidental Lewy body disease is pre-symptomatic Parkinson\u2019s disease","volume":"115","author":"Dickson","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S221","DOI":"10.1016\/S1353-8020(08)70005-1","article-title":"Neuropathology of Parkinson\u2019s disease dementia and dementia with Lewy bodies with reference to striatal pathology","volume":"13","author":"Tsuboi","year":"2007","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1212\/01.wnl.0000187889.17253.b1","article-title":"Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium","volume":"65","author":"McKeith","year":"2005","journal-title":"Neurology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1212\/01.wnl.0000306697.48738.b6","article-title":"Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort","volume":"70","author":"Zaccai","year":"2008","journal-title":"Neurology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0304-3940(98)00504-7","article-title":"Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson\u2019s disease and dementia with Lewy bodies","volume":"251","author":"Spillantini","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1212\/01.wnl.0000324625.00404.15","article-title":"Second consensus statement on the diagnosis of multiple system atrophy","volume":"71","author":"Gilman","year":"2008","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40035-020-0185-5","article-title":"Insights into the pathogenesis of multiple system atrophy: Focus on glial cytoplasmic inclusions","volume":"9","author":"Kaji","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1093\/brain\/awv114","article-title":"Expanding the spectrum of neuronal pathology in multiple system atrophy","volume":"138","author":"Cykowski","year":"2015","journal-title":"Brain"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1093\/jnen\/59.9.830","article-title":"Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy","volume":"59","author":"Duda","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/nan.12362","article-title":"Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type","volume":"43","author":"Brettschneider","year":"2017","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00401-008-0398-7","article-title":"Glial cytoplasmic inclusions in neurologically normal elderly: Prodromal multiple system atrophy?","volume":"116","author":"Fujishiro","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/bpa.12839","article-title":"Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease","volume":"30","author":"Koga","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s004010050693","article-title":"The distribution of Lewy bodies in pure autonomic failure: Autopsy findings and review of the literature","volume":"94","author":"Hague","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nm1746","article-title":"Lewy bodies in grafted neurons in subjects with Parkinson\u2019s disease suggest host-to-graft disease propagation","volume":"14","author":"Li","year":"2008","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/npp.2008.161","article-title":"Lewy body pathology in long-term fetal nigral transplants: Is Parkinson\u2019s disease transmitted from one neural system to another?","volume":"34","author":"Kordower","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00401-015-1485-1","article-title":"Propagation of alpha-synuclein pathology: Hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies","volume":"131","author":"Uchihara","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/brain\/aww230","article-title":"Like prions: The propagation of aggregated tau and \u03b1-synuclein in neurodegeneration","volume":"140","author":"Goedert","year":"2017","journal-title":"Brain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1002\/ana.24648","article-title":"Pathological \u03b1-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients","volume":"79","author":"Stokholm","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"67","DOI":"10.14802\/jmd.18067","article-title":"Altered Gut Microbiome and Intestinal Pathology in Parkinson\u2019s Disease","volume":"12","author":"Chiang","year":"2019","journal-title":"J. Mov. Disord."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Skj\u00e6rb\u00e6k, C., Knudsen, K., Horsager, J., and Borghammer, P. (2021). Gastrointestinal Dysfunction in Parkinson\u2019s Disease. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030493"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1093\/brain\/awm302","article-title":"Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson\u2019s disease","volume":"131","author":"Orimo","year":"2008","journal-title":"Brain"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3988\/jcn.2019.15.2.135","article-title":"Alpha-Synuclein in Skin Nerve Fibers as a Biomarker for Alpha-Synucleinopathies","volume":"15","author":"Kim","year":"2019","journal-title":"J. Clin. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1002\/mds.28126","article-title":"Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson\u2019s Disease With Orthostatic Hypotension","volume":"35","author":"Donadio","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"105332","DOI":"10.1016\/j.nbd.2021.105332","article-title":"Dermal and cardiac autonomic fiber involvement in Parkinson\u2019s disease and multiple system atrophy","volume":"153","author":"Brumberg","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1212\/WNL.0000000000004496","article-title":"REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease","volume":"89","author":"Clairembault","year":"2017","journal-title":"Neurology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1093\/jnen\/nly074","article-title":"Skin Nerve Phosphorylated \u03b1-Synuclein Deposits in Parkinson Disease with Orthostatic Hypotension","volume":"77","author":"Donadio","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"vii42","DOI":"10.1007\/s00415-006-7010-7","article-title":"Sweating dysfunctions in Parkinson\u2019s disease","volume":"253","author":"Hirayama","year":"2006","journal-title":"J. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.parkreldis.2007.09.002","article-title":"Nonmotor symptoms of Parkinson\u2019s disease: Prevalence and awareness of patients and families","volume":"14","author":"Cheon","year":"2008","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cger.2019.09.002","article-title":"Orthostatic Hypotension in Parkinson Disease","volume":"36","author":"Palma","year":"2020","journal-title":"Clin. Geriatr. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/S1474-4422(10)70213-1","article-title":"Are synucleinopathies prion-like disorders?","volume":"9","author":"Angot","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Jan, A., Gon\u00e7alves, N.P., Vaegter, C.B., Jensen, P.H., and Ferreira, N. (2021). The Prion-Like Spreading of Alpha-Synuclein in Parkinson\u2019s Disease: Update on Models and Hypotheses. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158338"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40478-021-01131-8","article-title":"Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain","volume":"9","author":"Ferreira","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00702-002-0808-2","article-title":"Idiopathic Parkinson\u2019s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen","volume":"110","author":"Braak","year":"2003","journal-title":"J. Neural Transm."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Pan-Montojo, F., Anichtchik, O., Dening, Y., Knels, L., Pursche, S., Jung, R., Jackson, S., Gille, G., Spillantini, M.G., and Reichmann, H. (2010). Progression of Parkinson\u2019s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE, 5.","DOI":"10.1038\/npre.2010.3352.3"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00401-019-02040-w","article-title":"Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats","volume":"138","author":"Ferreira","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/brain\/awab061","article-title":"Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats","volume":"144","author":"Ferreira","year":"2021","journal-title":"Brain"},{"key":"ref_84","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_85","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/ana.24448","article-title":"Vagotomy and subsequent risk of Parkinson\u2019s disease","volume":"78","author":"Svensson","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1212\/WNL.0000000000003961","article-title":"Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study","volume":"88","author":"Liu","year":"2017","journal-title":"Neurology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s00401-008-0346-6","article-title":"Applicability of current staging\/categorization of alpha-synuclein pathology and their clinical relevance","volume":"115","author":"Parkkinen","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00702-018-1898-9","article-title":"Is Braak staging valid for all types of Parkinson\u2019s disease?","volume":"126","author":"Jellinger","year":"2019","journal-title":"J. Neural Transm."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s00401-019-02071-3","article-title":"Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: A population-based study of Finns aged 85","volume":"138","author":"Raunio","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"S281","DOI":"10.3233\/JPD-191721","article-title":"Brain-First versus Gut-First Parkinson\u2019s Disease: A Hypothesis","volume":"9","author":"Borghammer","year":"2019","journal-title":"J. Parkinsons. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1093\/brain\/awaa238","article-title":"Brain-first versus body-first Parkinson\u2019s disease: A multimodal imaging case-control study","volume":"143","author":"Horsager","year":"2020","journal-title":"Brain"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/nrneurol.2017.157","article-title":"Idiopathic REM sleep behaviour disorder and neurodegeneration\u2014An update","volume":"14","author":"Stefani","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s10286-020-00674-5","article-title":"Autonomic dysfunction and phenoconversion in idiopathic REM sleep behavior disorder","volume":"30","author":"McCarter","year":"2020","journal-title":"Clin. Auton. Res. Off. J. Clin. Auton. Res. Soc."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.parkreldis.2020.05.013","article-title":"Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder\u2014A PET study","volume":"75","author":"Andersen","year":"2020","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3233\/JPD-212761","article-title":"Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson\u2019s Disease Subtypes","volume":"11","author":"Knudsen","year":"2021","journal-title":"J. Parkinsons. Dis."},{"key":"ref_96","first-page":"105599","article-title":"Animal models of brain-first and body-first Parkinson\u2019s disease","volume":"163","author":"Ulusoy","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"108870","DOI":"10.1016\/j.neuropharm.2021.108870","article-title":"Targeting alpha-synuclein via the immune system in Parkinson\u2019s disease: Current vaccine therapies","volume":"202","author":"Fleming","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_98","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_99","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3389\/fneur.2017.00013","article-title":"RNA Interference of Human \u03b1-Synuclein in Mouse","volume":"8","author":"Kim","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/mds.26477","article-title":"Autophagy and Alpha-Synuclein: Relevance to Parkinson\u2019s Disease and Related Synucleopathies","volume":"31","author":"Xilouri","year":"2016","journal-title":"Mov. Disord."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.4103\/1673-5374.284993","article-title":"Small molecules to prevent the neurodegeneration caused by \u03b1-synuclein aggregation","volume":"15","author":"Pujols","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1002\/mds.28218","article-title":"A Phase 1 Randomized Trial of Specific Active \u03b1-Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy","volume":"35","author":"Meissner","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00401-021-02381-5","article-title":"Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric \u03b1-synuclein accumulation in the brain and gut","volume":"143","author":"Nimmo","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature22815","article-title":"T cells from patients with Parkinson\u2019s disease recognize \u03b1-synuclein peptides","volume":"546","author":"Sulzer","year":"2017","journal-title":"Nature"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1038\/s41467-020-15626-w","article-title":"\u03b1-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson\u2019s disease","volume":"11","author":"Dhanwani","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_106","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_107","doi-asserted-by":"crossref","first-page":"13454","DOI":"10.1523\/JNEUROSCI.1292-12.2012","article-title":"Antibody-aided clearance of extracellular \u03b1-synuclein prevents cell-to-cell aggregate transmission","volume":"32","author":"Bae","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_108","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_109","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.nbd.2014.05.009","article-title":"Immunotherapy targeting \u03b1-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] \u03b1-synuclein mice","volume":"69","author":"Fagerqvist","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Shahaduzzaman, M., Nash, K., Hudson, C., Sharif, M., Grimmig, B., Lin, X., Bai, G., Liu, H., Ugen, K.E., and Cao, C. (2015). Anti-human \u03b1-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-\u03b1-synuclein rat model of Parkinson\u2019s disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116841"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.nbd.2017.05.002","article-title":"Differential effects of immunotherapy with antibodies targeting \u03b1-synuclein oligomers and fibrils in a transgenic model of synucleinopathy","volume":"104","author":"Overk","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40478-016-0410-8","article-title":"Anti-\u03b1-synuclein immunotherapy reduces \u03b1-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy","volume":"5","author":"Spencer","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"452","DOI":"10.3389\/fnins.2018.00452","article-title":"Region-Specific Effects of Immunotherapy with Antibodies Targeting \u03b1-synuclein in a Transgenic Model of Synucleinopathy","volume":"12","author":"Kallab","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"104582","DOI":"10.1016\/j.nbd.2019.104582","article-title":"Preclinical development of a high affinity \u03b1-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular \u03b1-synuclein and attenuate \u03b1-synuclein spreading in vivo","volume":"132","author":"Schofield","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.nbd.2018.11.024","article-title":"Naturally occurring autoantibodies against \u03b1-synuclein rescues memory and motor deficits and attenuates \u03b1-synuclein pathology in mouse model of Parkinson\u2019s disease","volume":"124","author":"Huang","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"104712","DOI":"10.1016\/j.nbd.2019.104712","article-title":"Characterization of novel conformation-selective \u03b1-synuclein antibodies as potential immunotherapeutic agents for Parkinson\u2019s disease","volume":"136","author":"Henderson","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_117","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_118","doi-asserted-by":"crossref","unstructured":"Chen, Y.-H., Wu, K.-J., Hsieh, W., Harvey, B.K., Hoffer, B.J., Wang, Y., and Yu, S.-J. (2021). Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein. Genes, 12.","DOI":"10.3390\/genes12060948"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"105543","DOI":"10.1016\/j.nbd.2021.105543","article-title":"ABBV-0805, a novel antibody selective for soluble aggregated \u03b1-synuclein, prolongs lifespan and prevents buildup of \u03b1-synuclein pathology in mouse models of Parkinson\u2019s disease","volume":"161","author":"Eriksson","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2005.05.010","article-title":"Effects of alpha-synuclein immunization in a mouse model of Parkinson\u2019s disease","volume":"46","author":"Masliah","year":"2005","journal-title":"Neuron"},{"key":"ref_121","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_122","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.1523\/JNEUROSCI.20-17-06365.2000","article-title":"Subcellular localization of wild-type and Parkinson\u2019s disease-associated mutant alpha -synuclein in human and transgenic mouse brain","volume":"20","author":"Kahle","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1093\/hmg\/ddq038","article-title":"Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes","volume":"19","author":"Kuo","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"bvz039","DOI":"10.1210\/jendso\/bvz039","article-title":"Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development","volume":"4","author":"Ghosh","year":"2020","journal-title":"J. Endocr. Soc."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"S323","DOI":"10.3233\/JPD-191707","article-title":"The Intestinal Barrier in Parkinson\u2019s Disease: Current State of Knowledge","volume":"9","author":"Derkinderen","year":"2019","journal-title":"J. Parkinsons. Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"S297","DOI":"10.3233\/JPD-191711","article-title":"Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson\u2019s Disease: A Systematic Review","volume":"9","author":"Boertien","year":"2019","journal-title":"J. Parkinsons. Dis."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"S331","DOI":"10.3233\/JPD-191729","article-title":"Inflammatory Bowel Diseases and Parkinson\u2019s Disease","volume":"9","author":"Brudek","year":"2019","journal-title":"J. Parkinsons. Dis."},{"key":"ref_128","first-page":"408","article-title":"Inflammatory bowel disease and Parkinson\u2019s disease: Common pathophysiological links","volume":"70","author":"Lee","year":"2021","journal-title":"Gut"},{"key":"ref_129","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_130","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3233\/JPD-171131","article-title":"Gastrointestinal Transit Time in Parkinson\u2019s Disease Using a Magnetic Tracking System","volume":"7","author":"Knudsen","year":"2017","journal-title":"J. Parkinsons. Dis."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:04:52Z","timestamp":1760133892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,20]]},"references-count":130,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["biom12020168"],"URL":"https:\/\/doi.org\/10.3390\/biom12020168","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,20]]}}}