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.