Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases - Genetic mutations in ATXN1, which encodes ataxin-1 protein, have been implicated in several distinct neurodegenerative diseases. In humans, wild-type ATXN1 alleles normally contain between 4-36 consecutive CAG codons in the polyglutamine tract of the first coding exon, with those containing greater than 21 repeats typically also carrying 1 to 3 interrupting CAT codons. The expansion of the repeat tract of one ATXN1 allele to 39 or more uninterrupted repeats results in the highly penetrant, late-onset, and progressive cerebellar ataxia called spinocerebellar ataxia type 1 (SCA1). Interestingly, intermediate length expansions of ATXN1 are associated with an increased risk for developing sporadic amyotrophic lateral sclerosis and a form of frontotemporal dementia (FTD) called progressive nonfluent aphasia (PNFA), while intronic mutations that decrease ATXN1 levels also increase risk for Alzheimer’s disease (AD) and multiple sclerosis. Although ATXN1 is ubiquitously expressed in many different cell types throughout the central nervous system, most studies have primarily focused on the role of mutant ataxin-1 in the cerebellar Purkinje cells (PCs), the most obvious population of neurons to degenerate in SCA1. Therefore, the functions of ataxin-1 and the effects of different ataxin-1 mutations in other populations beyond PCs are not well-known. Furthermore, effective disease-modifying therapies for any of these neurodegenerative disorders associated with ATXN1 mutations, including SCA1, FTD, and AD, are extremely limited or non-existent. Recently, we have identified profound alterations in oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) at early stages of SCA1 mice, which emerge around the onset of behavioral impairments and much earlier than PC degeneration. In this proposal, we plan to determine the precise impact of oligodendroglial deficits on neurodegenerative diseases, and to elucidate the mechanisms through which mutant and wild-type ataxin-1 regulate oligodendroglial differentiation and function. Aim 1 will employ conditional mouse genetic approaches to determine the degree to which oligodendroglial dysfunction contributes to different disease-related phenotypes using SCA1 as a model. Aim 2 will determine the cellular and molecular mechanisms through which ataxin-1 regulates oligodendroglial differentiation and function in the nervous system using in vivo and in vitro approaches. Aim 3 will expand the scope of the proposed study to human tissues and cells to examine oligodendroglial phenotypes. We anticipate that the research aims will provide fundamental insights into the role of oligodendroglia in neurodegenerative disease pathogenesis and progression, and uncover new mechanisms through which OPC differentiation into OLs is regulated. If successful, these studies will advance the importance of examining non-neuronal contributions to neurodegenerative diseases and reveal novel potential entry points for therapeutic intervention in disorders in which ATXN1 mutations are associated, including SCA1, FTD, and AD.
