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 and Sreeganga. S. Chandra ()
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D. J. Vidyadhara: Yale University
David Bäckström: Yale University
Risha Chakraborty: Yale University
Jiapeng Ruan: Yale University
Jae-Min Park: Yale University
Pramod K. Mistry: Yale University
Sreeganga. S. Chandra: Yale University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63444-9

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