{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:26:36Z","timestamp":1787052396045,"version":"build-2736575974"},"reference-count":117,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the heritable risk architecture of DLB: the \u03b1-synuclein gene SNCA, in which both copy-number variation and missense mutations exert dose- and conformation-dependent effects, and GBA1, encoding the lysosomal hydrolase glucocerebrosidase (GCase), the single most influential genetic risk factor for the disease. Here we synthesise evidence that these loci converge on a shared pathogenic endpoint\u2014the impairment of activity-dependent synaptic plasticity. We argue that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic \u03b1-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications. These proteoforms are trafficked to, and enriched within, presynaptic terminals, where they disrupt SNARE-complex assembly and synaptic-vesicle dynamics, while postsynaptically they perturb NMDA and AMPA receptor trafficking, dysregulate dendritic calcium, and compromise synaptic mitochondrial bioenergetics. The net consequence is a metaplastic shift away from long-term potentiation (LTP) and toward aberrant long-term depression (LTD), a signature of synaptic failure detectable before frank pathology. We map these molecular events onto disease-relevant circuits\u2014particularly the cholinergic basal forebrain and hippocampal\u2013cortical and thalamocortical networks\u2014and relate them to the defining neuropsychiatric features of DLB, including cognitive fluctuations and recurrent visual hallucinations. Finally, we evaluate emerging therapeutic strategies that target the GBA1\u2013\u03b1-synuclein axis and that aim to restore synaptic plasticity directly. Positioning DLB within the framework of genetically determined plasticity deficits clarifies its kinship with other neuropsychiatric disorders and identifies the synapse as the most tractable node for early, disease-modifying intervention. We further examine how GBA1 allele severity and zygosity grade the phenotype, which genetic and environmental factors modify penetrance in carriers, and what distinguishes this synaptopathy from those driven by PSEN1\/PSEN2, MAPT, or HTT, and we summarise the therapeutic pipeline\u2014including enzyme augmentation and adeno-associated viral GBA1 gene therapy\u2014that targets it.<\/jats:p>","DOI":"10.3390\/genes17080965","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:22:52Z","timestamp":1787048572000},"page":"965","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Architecture of Synaptic Failure in Dementia with Lewy Bodies: From \u03b1-Synuclein Proteoforms to GBA1-Mediated Plasticity Deficits"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-8711","authenticated-orcid":false,"given":"Anastasia","family":"Bougea","sequence":"first","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","article-title":"Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium","volume":"89","author":"McKeith","year":"2017","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13024-019-0306-8","article-title":"Dementia with Lewy bodies: An update and outlook","volume":"14","author":"Outeiro","year":"2019","journal-title":"Mol. 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