{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Vidyadhara DJ"],"funding":["Parkinson's Foundation","U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)","U.S. Department of Defense","U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)","U.S. Department of Defense (United States Department of Defense)","NINDS NIH HHS","Parkinson's Foundation (Parkinson's Foundation, Inc.)","Michael J. Fox Foundation for Parkinson's Research"],"pagination":["8484"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12475166"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(1)"],"pubmed_abstract":["GBA is the major risk gene for Parkinson's disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibit both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho-α-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis pathway defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validate these findings. Our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, involving dysfunction in SV endocytosis."],"journal":["Nature communications"],"pubmed_title":["Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson's disease and dementia with Lewy bodies."],"pmcid":["PMC12475166"],"funding_grant_id":["W81XWH-19-1-0264","MJFF-020160","RF1 NS110354","PF-RCE-1946","1RF1NS110354-01"],"pubmed_authors":["Vidyadhara DJ","Ruan J","Chandra SS","Park JM","Chakraborty R","Mistry PK","Backstrom D"],"additional_accession":[]},"is_claimable":false,"name":"Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson's disease and dementia with Lewy bodies.","description":"GBA is the major risk gene for Parkinson's disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibit both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho-α-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis pathway defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validate these findings. Our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, involving dysfunction in SV endocytosis.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-03T22:48:33.86Z","creation":"2026-05-02T03:11:46.45Z"},"accession":"S-EPMC12475166","cross_references":{"pubmed":["41006254"],"doi":["10.1038/s41467-025-63444-9"]}}