{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:05:48Z","timestamp":1784261148317,"version":"3.55.0"},"reference-count":102,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Neurol Disord"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:p>Parkinson\u2019s disease (PD) remains the second most common neurodegenerative disorder globally, yet disease-modifying therapies remain elusive. The past decade of therapeutic development has been dominated by the hypothesis that alpha-synuclein aggregates spread in a prion-like manner. This catalysed the development of immunotherapy approaches targeting extracellular alpha-synuclein. However, high-profile Phase II and III clinical trials, such as those for cinpanemab and prasinezumab, failed to demonstrate clinical efficacy. This narrative review evaluates alpha-synuclein-targeted immunotherapies, their mechanistic rationale, the underlying reasons for recent clinical trial failures and to propose alternative metabolic frameworks. A literature search of peer-reviewed articles published up to 10 December 2025 was performed using the PubMed database to evaluate immunotherapies, mechanistic models and trial failures in PD. The prevailing \u2018prion-like\u2019 spread hypothesis may be overemphasised in the context of human disease. We propose the \u2018Single-Neuron Degeneration Hypothesis\u2019, suggesting that PD pathology is primarily driven by intracellular autotoxicity \u2013 specifically involving the dopamine metabolite aminochrome, mitochondrial dysfunction and oxidative stress \u2013 occurring independently within each dopaminergic neuron. Multifactorial contributors to trial failure include the inadequacy of preclinical models such as MPTP, the insensitivity of the MDS-UPDRS, diagnostic heterogeneity and the statistical reality of neuronal loss rates. Future therapeutic strategies must integrate intracellular neuroprotection alongside extracellular clearance approaches, with significantly earlier intervention.<\/jats:p>","DOI":"10.1177\/17562864261465665","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T12:35:11Z","timestamp":1784032511000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["The conundrum of alpha-synuclein antibody failures in Parkinson\u2019s disease: a narrative review of mechanisms and alternative metabolic hypotheses"],"prefix":"10.1177","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-8711","authenticated-orcid":false,"given":"Anastasia","family":"Bougea","sequence":"first","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, 72-74 Vasilissis Sofias Avenue, Athens 11528, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam9080"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.11.001"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11111732"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071687"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12071012"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9112495"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21228645"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2020.01.019"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-024-02863-2"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-023-03904-0"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-031521-034145"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30287-X"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102480"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030771"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1080\/00207454.2017.1403916"},{"issue":"2","key":"e_1_3_4_19_2","first-page":"111","article-title":"Erythrocyte antioxidant enzymes in Parkinson\u2019s disease","volume":"121","author":"Abraham S","year":"2005","unstructured":"Abraham S, Soundararajan CC, Vivekanandhan S, et al. 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