Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies
D. J. Vidyadhara, David Bäckström, Risha Chakraborty, Jiapeng Ruan, Jae-Min Park, Pramod K. Mistry, Sreeganga S. Chandra
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. GBA, a major gene for Parkinson’s disease and dementia with Lewy bodies, is associated with increased risk of developing dementia. Here, we demonstrate that GBA mutations in mice contribute to cognitive deficits through α-synuclein-independent mechanisms that impact synaptic vesicle endocytosis.