Investigators: Henry Paulson, Maria do Carmo Pereira da Costa, Yuanfang Guan
Funding: National Institute of Neurological Disorders and Stroke, 2015-2020 (2 R01 NS 038712 17)
This competing renewal application seeks to understand and develop treatments for Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease (MJD). SCA3 is one of nine hereditary neurodegenerative diseases caused by CAG repeat expansions that encode abnormally long polyglutamine tracks in the disease proteins. A fatal and incurable disorder, SCA3 may be the most common polyglutamine disease in the world. Thus, the unmet needs are tremendous for this particular disorder and for all other polyglutamine diseases. The current proposal moves from our prior mechanistic focus to a complementary set of mechanistic and translational studies. Our central hypothesis is that the mutant SCA3 disease protein, ATXN3, is toxic due to its tendency to misfold and aggregate, implying that efforts to reduce levels of this toxic protein will be an effective route to preventive therapy. Our primary objective is to identify strategies to reduce levels of this toxic disease protein so that we can achieve our long-term goal of developing effective preventive therapy for SCA3 and other polyglutamine diseases. Aim 1 will address a central, unanswered question in all polyglutamine diseases: What is the relationship between the process of polyQ disease protein misfolding and aggregation on the one hand, and the process of neuronal dysfunction and degeneration on the other hand? Aim 1 will take advantage of newly developed knock-in mouse models of SCA3 to test the hypothesis that the aggregation propensity of mutant ATXN3 directly contributes to toxicity, driving downstream molecular events that contribute to disease pathogenesis. A direct comparison between two otherwise essentially identical knock-in mouse models -- one of which is aggregation-prone and the other one not ? will allow us to define the potential causal relationship between disease protein aggregation and molecular correlates of disease, including alterations in neuronal gene expression, disease protein proteolysis, and aberrant protein-protein interactions (). Aim 2 will seek to define the genes and pathways that regulate cellular levels of ATXN3 in neurons, based on our central hypothesis that the primary toxic entity in SCA3 is mutant ATXN3. Aim 2 takes advantage both of a recent RNAi screen to identify genes that modulate ATXN3 and of growing understanding of how specific ATXN3 interactors influence levels of the disease protein (). ?Druggable? genes and molecular pathways identified in Aim 2 are likely to include attractive targets for therapeutic strategies to reduce levels of the disease protein in SCA3 and possibly related polyglutamine diseases. Aim 3 takes the view that a particularly effective therapeutic strategy for SCA3 and other polyglutamine diseases is to target proximal steps in the pathogenic cascade. Specifically, Aim 3 will test the efficacy of broad CNS delivery of antisense oligonucleotides targeting human ATXN3, in a controlled preclinical trial in SCA3 transgenic mice expressing the full human ATXN3 disease gene. The complementary nature of the aims, coupled with the combined mechanistic and translational emphasis, enhances the potential impact of the proposed studies. In particular, the preclinical mouse trial in Aim 3, if successful, will encourage future studies to translate this therapeutic strategy to the ataxia clinic.