Cellular and Molecular basis for cognitive impairment associated with Glucocerebrosidase (GBA1) mutation

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ABSTRACT Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson's disease (PD), which negatively affects patient's functional capacity, quality of life and ultimately lifespan. The mechanisms underlying cognitive impairment in PD are largely undefined, limiting treatment and prevention strategies. This project is designed to advance our understanding of the cellular and molecular basis of the cognitive impairment associated with heterozygous mutations in GBA1, a susceptibility gene for Parkinson's disease (PD) that encodes for the lysosome hydrolase glucocerebrosidase (GCase). Homozygous GBA1 mutations cause Gaucher disease(GD), the most common lysosome storage disorder, whereas heterozygous mutations of GBA1 constitute the strongest genetic risk factor for PD. While accumulating evidence suggests that GBA1 mutations exacerbate cognitive impairment and Lewy body pathology in PD, the mechanisms remain unknown. Our preliminary results revealed impaired hippocampal synaptic plasticity and cognitive dysfunction in a L444P mutant GBA1 heterozygous knockin (GBA1L444P/WT) mouse model. The GBA1L444P/WT mice showed hippocampal accumulation of α-synuclein (αSyn) and altered lipid profiles. Based on these preliminary findings, we hypothesize that the L444P GBA1 mutation disrupts synaptic and cognitive function through αSyn accumulation and/or lipid changes, and that the L444P GBA1 mutation interacts with PD related insults, e.g., abnormal αSyn accumulation, to accelerate cognitive decline. Our specific aims are (1) to characterize pre- and post-synaptic changes that underlie impaired hippocampal synaptic plasticity in the GBA1L444P/WT mice; (2) to identify molecular and cellular mechanisms of synaptic and cognitive impairment in the GBA1L444P/WT mice; and (3) to determine whether the GBA1 mutation exacerbates αSyn pathology, neuronal loss, synaptic and cognitive impairment in a Thy1-αSyn pre-manifest PD mouse model. Successful completion of this study will not only provide mechanistic insights into the key processes that underlie cognitive impairment caused by GBA1 mutations, but also deliver valuable animal models for interrogating neurodegenerative pathways in PD and for therapeutic screening.