Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies.

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. We investigated 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 showed early cognitive deficits but lacked PD-like motor deficits or α-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-α-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis defects in exci

SUBMITTER: Vidyadhara DJ 

PROVIDER: S-EPMC11527026 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature