This competing renewal application seeks to understand and develop treatments for Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease. SCA3 is one of nine inherited 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 great for this particular disorder and for all other polyglutamine diseases. The current proposal moves from our prior exclusively 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 o 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 leverages 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.
Aim 2 seeks to define the genes and pathways that regulate cellular levels of ATXN3 in neurons.
Aim 2 builds on our recent RNAi screen to identify genes that modulate ATXN3 and on a 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.
Aim 3 will test the efficacy of broad CNS delivery of antisense oligonucleotides targeting human ATXN3 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.

Public Health Relevance

The studies in this competing renewal application seek both to understand pathogenic mechanisms underlying the polyglutamine neurodegenerative disease, Spinocerebellar Ataxia type 3, and to advance the field toward preventive therapy for this currently untreatable and fatal disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Duda, Marlena; Zhang, Hongjiu; Li, Hong-Dong et al. (2018) Brain-specific functional relationship networks inform autism spectrum disorder gene prediction. Transl Psychiatry 8:56
McLoughlin, Hayley S; Moore, Lauren R; Chopra, Ravi et al. (2018) Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84:64-77
Sutton, Joanna R; Blount, Jessica R; Libohova, Kozeta et al. (2017) Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3. Hum Mol Genet 26:1419-1431
Ramani, Biswarathan; Panwar, Bharat; Moore, Lauren R et al. (2017) Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes. Hum Mol Genet 26:3362-3374
Ramani, Biswarathan; Harris, Ginny M; Huang, Rogerio et al. (2017) A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. Hum Mol Genet 26:3232-3233
Moore, Lauren R; Rajpal, Gautam; Dillingham, Ian T et al. (2017) Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Mol Ther Nucleic Acids 7:200-210
Costa, Maria do Carmo; Ashraf, Naila S; Fischer, Svetlana et al. (2016) Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3. Brain 139:2891-2908
Faggiano, Serena; Alfano, Caterina; Pastore, Annalisa (2016) The missing links to link ubiquitin: Methods for the enzymatic production of polyubiquitin chains. Anal Biochem 492:82-90
Ramani, Biswarathan; Harris, Ginny M; Huang, Rogerio et al. (2015) A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. Hum Mol Genet 24:1211-24
Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2015) Allosteric regulation of deubiquitylase activity through ubiquitination. Front Mol Biosci 2:2

Showing the most recent 10 out of 58 publications