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bioRxiv · 10.1101/2024.10.23.619548

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

Vidyadhara, D. J.·Backstrom, D.·Chakraborty, R.·Ruan, J.·Park, J.-M.·Mistry, P. K.·Chandra, S. S.
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Abstract

GBA is the major risk gene for Parkinsons disease (PD) and Dementia with Lewy Bodies (DLB), two common -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 -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--synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validated these findings. Our results indicate that Gba mutations, while exacerbating pre-existing -synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through -synuclein-independent mechanisms, involving dysfunction in SV endocytosis.

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Vidyadhara, D. J., Backstrom, D., Chakraborty, R., Ruan, J., Park, J.-M., Mistry, P. K., Chandra, S. S.. 2024-10-23. Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies. https://doi.org/10.1101/2024.10.23.619548

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