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We investigated the role of mutant\n                  <jats:italic>GBA<\/jats:italic>\n                  in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but lacked PD-like motor deficits or \u03b1-synuclein pathology. Conversely, SNCA tg mice displayed age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibited both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho-\u03b1-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validated these findings. Our results indicate that Gba mutations, while exacerbating pre-existing \u03b1-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through \u03b1-synuclein-independent mechanisms, involving dysfunction in SV endocytosis.\n                <\/jats:p>","DOI":"10.1101\/2024.10.23.619548","type":"posted-content","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T22:25:15Z","timestamp":1729722315000},"source":"Crossref","is-referenced-by-count":2,"title":["Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson\u2019s disease and Dementia with Lewy bodies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0974-0307","authenticated-orcid":false,"given":"D J","family":"Vidyadhara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"B\u00e4ckstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risha","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiapeng","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Min","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod K.","family":"Mistry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-1733","authenticated-orcid":false,"given":"Sreeganga. 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