A recent genetic study from our research group revealed that the Ataxin-1 gene (ATXN1) is genetically associated with Alzheimer's disease. ATXN1 encodes a nuclear protein, Ataxin-1, and DNA mutations that increase the CAG trinucleotide repeat in ATXN1 are known to cause spinocerebellar ataxia type 1 (SCA1). SCA1 is a neurodegenerative disease that primarily impairs coordinated movement and later deteriorates the cognitive function of patients. In a preliminary study with mouse models, we found the deletion of ATXN1 elevates BACE1 expression in the brain. BACE1 cleaves amyloid precursor protein (APP) and initiates the generation of amyloid beta, the main culprit in senile plaques in Alzheimer’s disease brains. In this proposed study, we will attempt to uncover the molecular mechanism by which Ataxin-1 regulates BACE1 expression and the amyloidogenic cleavage of APP in the brain. We will further investigate how Ataxin-1 affects Alzheimer’s disease-related phenotypes such as amyloid beta plaque deposition, altered neuron generation and axonal path-finding in the brain.
Role of ATXN1 in Regulating BACE1 Activity
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