Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by expansion of a CAG repeat that encodes glutamine in ATAXIN-1 (ATXN1). SCA1 is one of nine dominantly inherited disorders in which a polyglutamine expansion causes the disease protein to misfold, accumulate and exert various toxic functions. The ultimate goal of my lab is to understand SCA1 pathogenesis in order to develop effective therapeutic intervention for SCA1. Over the past five years, we have made a number of discoveries that deepen our understanding of SCA1 but also reveal it to be considerably more complex than anyone expected. First, we discovered that glutamine-expanded Ataxin-1 interacts with native protein partners to cause SCA1. Second, we identified the RNA-binding protein 17 (RBM17) as one of the proteins in the native ATXN1 complexes and found that interactions of RBM17 with mutant ATXN1 are augmented by both the CAG expansion and phosphorylation at serine 776 (a residue necessary for mutant ATXN1 to exert toxicity). Third, we discovered that both wild-type ATXN1 and its paralog ATAXIN-1Like (ATXN1L) are strong suppressors of SCA1 phenotypes, pointing to a complex pathogenetic process that may involve both gain- and loss-of-function;we also learned that ATXN1 and ATXN1L are functionally redundant. Fourth, we discovered that while the glutamine expansion enhances some ATXN1 interactions, it compromises others, which provides a mechanistic account of the combined gain- and loss-of-function. Fifth, we discovered that different ATXN1 complexes predominate in the brainstem and cerebellum (both of which are vulnerable in SCA1), which in turn suggests that a therapy targeted to neurons in one brain region may not work at all in another (as we demonstrated in an animal model). These results lead to us to propose that a) RBM17 mediates mutant ATXN1 toxicity in the cerebellum;b) the normal molecular function(s) of ATXN1 and ATXN1L, especially in the nervous system and adult brain, are critical to understanding how the glutamine expansion leads to the neurotoxicity;and c) the distribution and toxicity of mutant ATXN1 in the various brain regions affected in SCA1 is influenced by more than one or two key partners, identification of which is key to understanding the full picture of SCA1 pathogenesis. To test these hypotheses we will carry out the following aims: 1) Elucidate the function of RBM17 and the role of RNA processing in SCA1 pathogenesis;2) Characterize the in vivo functions of ATXN1 and its paralog ATXN1L in the mature nervous system;3) Characterize the molecular mechanisms that underlie differential neuronal vulnerability in SCA1. The knowledge we gain from these studies are likely to shed light on other neurodegenerative diseases, RNA biology, and role of RNA processing in neurobiology.
The burden of neurodegenerative disorders on public health is large and will continue to grow. Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease for which there is no therapy. The proposed studies will advance understanding of why neurons degenerate in SCA1 as well as other neurodegenerative diseases and will provide insight about interventions to outcome, which are essential for the translation of research into clinical treatments.
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