Our lab studies the pathogenesis of spinocerebellar ataxia type 1?a neurodegenerative disorder caused by a pathogenic polyglutamine expansion in the protein ataxin-1 (ATXN1). This supplemental application is inspired by novel links between ATXN1 and Alzheimer?s disease (AD) pathogenesis. Most notably, recent Genome Wide Association Studies (GWAS) have identified variants in the ATXN1 gene that influence AD risk; moreover, ATXN1 protein?both wild type and expanded?modulate the levels of beta-secretase 1 (BACE1), a key protease involved in the cleavage of Amyloid Protein Precursor (APP) that results in the production of the amyloidogenic peptide A beta. The overarching hypothesis of this application, therefore, is that there are common pathways in these two otherwise disparate proteinopathies. We envisage that our experiments testing this hypothesis will lead to novel insights particularly in combating cognitive decline in both these syndromes.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1 leading to accumulation of mutant ATXN1, while Alzheimer?s disease (AD) is caused by extracellular accumulation of beta amyloid that stems in part from BACE1 cleavage of APP. Recently, ATXN1 has been shown to regulate the expression of BACE1 and play a role in amyloid formation. This proposal tests the role of ATXN1 in AD pathogenesis and the role of BACE1 in SCA1 pathogenesis with the ultimate goal of finding areas of intersection between two otherwise unrelated degenerative syndromes.
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