{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:54:50Z","timestamp":1790639690526,"version":"4.1.0"},"reference-count":169,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"CONAHCYT","doi-asserted-by":"publisher","award":["CF-2023-G-107"],"award-info":[{"award-number":["CF-2023-G-107"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Evidence increasingly indicates that synaptic vesicle dysfunction emerges early in Parkinson\u2019s disease (PD), preceding overt dopaminergic neuron loss rather than arising solely as a downstream consequence of neurodegeneration. \u03b1-Synuclein (\u03b1Syn), a presynaptic protein that regulates vesicle clustering, trafficking, and neurotransmitter release under physiological conditions, exhibits dose-, conformation-, and context-dependent actions that distinguish its normal regulatory roles from pathological effects observed in disease models. This narrative review synthesizes findings from a structured search of PubMed and Scopus, with emphasis on \u03b1-syn-knockout (\u03b1SynKO) and BAC transgenic (\u03b1SynBAC) mouse models, which do not recapitulate the full human PD trajectory but provide complementary insights into \u03b1Syn physiological function and dosage-sensitive vulnerability. Priority was given to studies integrating ultrastructural approaches\u2014such as cryo-electron tomography, high-pressure freezing\/freeze-substitution TEM, and super-resolution microscopy\u2014with proteomic and lipidomic analyses. Across these methodologies, several convergent presynaptic alterations are consistently observed. In vivo and ex vivo studies associate \u03b1Syn perturbation with impaired vesicle acidification, consistent with altered expression or composition of vacuolar-type H+-ATPase subunits. Lipidomic analyses reveal age- and genotype-dependent remodeling of vesicle membrane lipids, particularly curvature- and charge-sensitive phospholipids, which may destabilize \u03b1Syn\u2013membrane interactions. Complementary biochemical and cell-based studies support disruption of SNARE complex assembly and nanoscale release-site organization, while ultrastructural analyses demonstrate reduced vesicle docking, altered active zone geometry, and vesicle pool disorganization, collectively indicating compromised presynaptic efficiency. These findings support a synapse-centered framework in which presynaptic dysfunction represents an early and mechanistically relevant feature of PD. Rather than advocating \u03b1Syn elimination, emerging therapeutic concepts emphasize preservation of physiological vesicle function\u2014through modulation of vesicle acidification, SNARE interactions, or membrane lipid homeostasis. Although such strategies remain exploratory, they identify the presynaptic terminal as a potential window for early intervention aimed at maintaining synaptic resilience and delaying functional decline in PD.<\/jats:p>","DOI":"10.3390\/brainsci16010007","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:22:27Z","timestamp":1766578947000},"page":"7","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synaptic Vesicle Disruption in Parkinson\u2019s Disease: Dual Roles of \u03b1-Synuclein and Emerging Therapeutic Targets"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2476-5214","authenticated-orcid":false,"given":"Mario","family":"Trevi\u00f1o","sequence":"first","affiliation":[{"name":"Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara 44130, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Guerra-Crespo","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Padilla-God\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Physics, Western Institute of Technology and Higher Education, Tlaquepaque 45604, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1667-2253","authenticated-orcid":false,"given":"Emmanuel","family":"Ortega-Robles","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Cl\u00ednica, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-7571","authenticated-orcid":false,"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Cl\u00ednica, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico"},{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cell.2006.10.030","article-title":"Molecular anatomy of a trafficking organelle","volume":"127","author":"Takamori","year":"2006","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1523\/JNEUROSCI.4074-09.2010","article-title":"Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein","volume":"30","author":"Gronborg","year":"2010","journal-title":"J. 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