{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:27:31Z","timestamp":1786440451737,"version":"build-2736575974"},"reference-count":188,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T00:00:00Z","timestamp":1786233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","award":["RRC-2026-23688274"],"award-info":[{"award-number":["RRC-2026-23688274"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Synaptic failure is the most accurate pathological correlate of cognitive and motor decline in neurodegenerative diseases. However, the molecular logic governing selective synaptic vulnerability in Alzheimer\u2019s (AD) and Parkinson\u2019s (PD) remains a fundamental enigma. This review dissects the hierarchical organization of the synaptome, arguing that synaptic decay is not a generic process of attrition but a specific collapse of subsynaptic domains (SSDs) and trans-synaptic nanocolumns, considered here within the framework of the tetrapartite synapse, which comprises the presynaptic and postsynaptic compartments together with glia and the perisynaptic extracellular matrix. We use the term pathological convergence in a restricted sense, to denote that, although the primary aggregates differ, the two diseases converge on the same postsynaptic scaffolding hubs and on a comparable loss of condensate fluidity. We propose a biophysical model where the Post-Synaptic Density (PSD) matrix, governed by liquid\u2013liquid phase separation (LLPS), may undergo a pathological liquid-to-solid transition\u2014characterized by condensate maturation and the formation of insoluble protein aggregates\u2014driven by proteotoxic species. Specifically, we analyze how A\u03b2-mediated zinc sequestration disrupts the Shank-SAM scaffold hierarchy in AD, while \u03b1-synuclein aggregates arrest presynaptic vesicle dynamics and mitochondrial homeostasis in PD. Furthermore, we explore the emerging frontier of \u201cPrecision Synaptopharmacology,\u201d highlighting how targeted modulation of protein\u2013protein interaction (PPIs), synthetic synaptic organizers (e.g., CPTX), and phase-stabilizing chaperones can restore nanocolumn alignment and synaptic fluidity. We also set out the principal limitations of these strategies, including blood\u2013brain barrier delivery, off-target effects, the immaturity of condensate-directed pharmacology and the incomplete translation of rodent findings to human disease, and we consider the vascular and peripheral contributions that modify the synaptic environment. By integrating recent advances in super-resolution microscopy, systems biology, and activity-based neurorehabilitation, we provide a comprehensive framework for shifting neuroprotective strategies toward the precision engineering and functional recovery of synaptic nano-architecture.<\/jats:p>","DOI":"10.3390\/cells15161433","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:20:03Z","timestamp":1786324803000},"page":"1433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Synaptic Diversity: Molecular Architectures, Phase Transitions, and Shared Postsynaptic Failure in Alzheimer\u2019s and Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-1455","authenticated-orcid":false,"given":"Giovanni Luca","family":"Cipriano","sequence":"first","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0215-2174","authenticated-orcid":false,"given":"Ivan","family":"Anchesi","sequence":"additional","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4084-6568","authenticated-orcid":false,"given":"Alessia","family":"Floramo","sequence":"additional","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9058-5755","authenticated-orcid":false,"given":"Veronica","family":"Argento","sequence":"additional","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7882-2432","authenticated-orcid":false,"given":"Maria Francesca","family":"Astorino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-9855","authenticated-orcid":false,"given":"Marco","family":"Calabr\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8771-0317","authenticated-orcid":false,"given":"Osvaldo","family":"Artimagnella","sequence":"additional","affiliation":[{"name":"Centro Neurolesi \u201cBonino-Pulejo\u201d, IRCCS, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.semcdb.2022.05.028","article-title":"Synapse Pathology in Alzheimer\u2019s Disease","volume":"139","author":"Griffiths","year":"2023","journal-title":"Semin Cell Dev. 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