biostudies-literatureVidyadhara DJParkinson's FoundationU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeMichael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)U.S. Department of DefenseU.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 HHSParkinson's Foundation (Parkinson's Foundation, Inc.)Michael J. Fox Foundation for Parkinson's Research8484https://www.ebi.ac.uk/biostudies/studies/S-EPMC12475166biostudies-literatureUnknown16(1)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.Nature communicationsSynaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson's disease and dementia with Lewy bodies.PMC12475166W81XWH-19-1-0264MJFF-020160RF1 NS110354PF-RCE-19461RF1NS110354-01Vidyadhara DJRuan JChandra SSPark JMChakraborty RMistry PKBackstrom DfalseSynaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson's disease and dementia with Lewy bodies.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.2025-01-01T00:00:00Z2025 Sep2026-06-03T22:48:33.86Z2026-05-02T03:11:46.45ZS-EPMC124751664100625410.1038/s41467-025-63444-9