{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:05:05Z","timestamp":1790805905656,"version":"4.1.0"},"reference-count":127,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is defined by the progressive degeneration of dopaminergic neurons within the substantia nigra and the pathological accumulation of \u03b1-synuclein (\u03b1-syn) aggregates. Beyond these intracellular hallmarks, the extracellular matrix (ECM) has emerged as an active regulator of synaptic dysfunction, neuroinflammation, and disease progression. Recent multi-omics evidence, including transcriptomic and proteomic profiling of post-mortem tissue and iPSC-derived neurons, demonstrates consistent dysregulation of ECM components across both sporadic and genetic PD subtypes\u2014typified by downregulation of basement membrane collagens (COL4A) and integrin signaling (ITGB1), alongside upregulation of matrix metalloproteinases (MMPs). These alterations destabilize perineuronal nets (PNNs), allow prion-like \u03b1-syn propagation, and promote glial activation through TLR-mediated signaling. Circulating ECM-derived neoepitopes (C1M, C4M) may complement neurofilament light chain as prognostic biomarkers of disease progression, although prospective validation remains necessary. Pharmacological strategies targeting MMP activity (e.g., doxycycline), integrin\u2013FAK signaling (ATN-161), and MMP\u2013TIMP balance (mesenchymal stem cells) represent emerging therapeutic avenues, though clinical evidence in PD remains limited. This review synthesizes current evidence on ECM dysregulation in PD and discusses its implications for biomarker development and disease-modifying intervention.<\/jats:p>","DOI":"10.3390\/life16061007","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dysregulation of the Extracellular Matrix in the Synaptic Pathology of Parkinson\u2019s Disease: Molecular Mechanisms and Novel Therapeutic Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-5043","authenticated-orcid":false,"given":"Carmen","family":"Rubio","sequence":"first","affiliation":[{"name":"Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4278-4814","authenticated-orcid":false,"given":"Ricardo","family":"P\u00e9rez-Rubio","sequence":"additional","affiliation":[{"name":"Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"},{"name":"Mexican Faculty of Medicine, La Salle University, Mexico City 14000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3184-6522","authenticated-orcid":false,"given":"Javier","family":"P\u00e9rez-Villavicencio","sequence":"additional","affiliation":[{"name":"Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"},{"name":"Department of Electrical Engineering, Basic Sciences and Engineering Division, Metropolitan Autonomous University, Iztapalapa Campus, Mexico City 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5859-2617","authenticated-orcid":false,"given":"Norma","family":"Serrano-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-3598","authenticated-orcid":false,"given":"\u00c1ngel","family":"Lee","sequence":"additional","affiliation":[{"name":"Public Health Intelligence Unit, National Institute of Public Health, Cuernavaca 62100, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Granados-Rojas","sequence":"additional","affiliation":[{"name":"Laboratory of Biomolecules and Infant Health, National Institute of Pediatrics, Mexico City 04530, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Tena-Suck","sequence":"additional","affiliation":[{"name":"Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"},{"name":"Pathology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9236-0609","authenticated-orcid":false,"given":"Mois\u00e9s","family":"Rubio-Osornio","sequence":"additional","affiliation":[{"name":"Neurochemistry Department, National Institute of Neurology and Neurosurgery, Av. 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