The effect of GBA1 L444P heterozygous mutation on synaptic morphology in the hippocampus and cognition related to Lewy body dementias

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Project Summary/Abstract: Nearly 80% of Parkinson’s disease (PD) patients develop dementia. PD is pathologically characterized by the accumulation of insoluble aggregates of misfolded α-syn called Lewy bodies and Lewy neurites. The most common genetic risk factor of PD is mutations in the GBA1 gene, which encodes for the lysosomal enzyme glucocerebrosidase (GCase). PD patients with GBA1 mutations (GBA1-PD) show increased risk of dementia and abundant Lewy pathology. Model systems show that expression of mutant GCase increases formation of pathologic α-syn. These data suggest an interaction among mutant GCase, α-syn inclusion formation, and cognitive deficits. PD patients heterozygous for the severe GBA1 L444P mutation (GBA+/L444P) have one of the highest risks of developing dementia (5.6-fold compared to noncarrier of the GBA mutation). GCase produced from GBA1 L444P is not properly folded or trafficked from the endoplasmic reticulum to lysosomes, and data suggest that impaired lysosome function leads to an accumulation of α-syn, which forms pathologic inclusions. Abnormal lysosome activity caused by mutant GBA1 may also impact synaptic structure. The lysosomal enzyme, Cathepsin B (CatB) has been genetically linked to GBA1-PD. Levels of CatB are reduced in the brains of GBA+/L444P mice. Impaired cleavage of α-syn by CatB may lead to an accumulation of α-syn. Thus, the overall goal of this project is to evaluate synaptic degeneration and identify the mechanistic role of CatB activity behind enhanced α-syn aggregation and synaptic changes in the hippocampus of GBA1+/L444P mice. We have found that GBA1+/L444P mice show significantly increased formation of α-syn inclusions, only in the hippocampus. My lab found that early formation of α-syn inclusions in primary hippocampal neurons and in wildtype mice leads to a major loss of excitatory synapses. I propose that α-syn inclusions formation in the hippocampus causes major changes in synaptic structure, enhanced by expression of GBA1+/L444P. My central hypothesis is that decreased CatB expression and activity caused by GBA1+/L444P expression increases the formation of α-syn inclusions, which leads to synaptic degeneration and cognitive impairments. I will test this hypothesis by determining if the GBA1+/L444P mutation enhances synaptic degeneration and leads to cognitive deficits caused by α-synuclein inclusions in the hippocampus. I will also determine if reduced activity of CatB in the hippocampus of GBA+/L444P mice enhances α-syn aggregation. Understanding these mechanisms will lead to therapies designed to modulate enzymatic activity in PD and other synucleinopathies. Through this proposed work, I will continue to learn valuable techniques, such as expansion microscopy to analyze details of synaptic structure, and the use of AAV viruses to increase levels of GCase and CatB, which will allow us to better understand molecular mechanisms that lead to PD. I will also collaborate with experts in GBA1 mutations and neurodegeneration.