Spinocerebellar Ataxia Type 3 (SCA3, also known as Machado-Joseph Disease) belongs to the family of polyglutamine-dependent neurodegenerative disorders that also includes Huntington's Disease and several other SCAs. SCA3, which is the most common dominant ataxia in the world, is caused by large expansions in the polyglutamine tract of the protein ataxin-3. Current therapeutic approaches for the treatment of SCA3 are symptomatic and do not address the core etiology. Animal models of polyglutamine diseases have shown that reducing the levels of the causative protein leads to significant improvement in neuronal pathology and symptoms. This suggests that enhancing the degradation of the ataxin-3 protein provides a reasonable approach to treat SCA3. The long-term goal of my laboratory is to elucidate molecular mechanisms involved in neurodegeneration and neuroprotection. Starting during my postdoctoral work, I focused on pathways involved in protein degradation, and specifically on ataxin-3. In the course of trying to understand the cell biology of ataxin-3 as a point of entry for SCA3 therapy, we made the unexpected finding that the degradation of ataxin-3 is not regulated by ubiquitination in the common sense. Instead, pathogenic ataxin-3 is stabilized by its interaction with the proteasomal shuttle proteins Rad23 and VCP. Our novel finding provided a lead to destabilize pathogenic ataxin-3 for therapy. This strategy is made even more plausible by the ability of cells and organisms to tolerate very low levels of ataxin-3 - in other words, without a restrictive therapeutic window in terms of the cellular levels of ataxin-3. Here, we propose to expand on these exciting findings by determining how ataxin-3 is degraded, with special emphasis on Rad23 and VCP, and by subsequently testing the idea that disrupting these interactions suppresses ataxin-3-dependent degeneration in the genetically tractable model organism Drosophila melanogaster. We then plan to take advantage of this model system to discover novel genes that suppress ataxin-3-dependent degeneration.

Public Health Relevance

Age-dependent neurodegeneration is a major health issue that will worsen as people live longer lives. Mechanisms of neurodegeneration and protective pathways to combat disease are poorly understood. We propose to elucidate the function of specific proteins and cellular pathways that can be used to provide protection from neurodegenerative processes.

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
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
Ristic, Gorica; Tsou, Wei-Ling; Guzi, Ermal et al. (2016) USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila. J Biol Chem 291:9161-72
Tsou, Wei-Ling; Hosking, Ryan R; Burr, Aaron A et al. (2015) DnaJ-1 and karyopherin α3 suppress degeneration in a new Drosophila model of Spinocerebellar Ataxia Type 6. Hum Mol Genet 24:4385-96
Tsou, Wei-Ling; Ouyang, Michelle; Hosking, Ryan R et al. (2015) The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster. Neurobiol Dis 82:12-21
Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2015) Allosteric regulation of deubiquitylase activity through ubiquitination. Front Mol Biosci 2:2
Blount, Jessica R; Tsou, Wei-Ling; Ristic, Gorica et al. (2014) Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun 5:4638
Ristic, Gorica; Tsou, Wei-Ling; Todi, Sokol V (2014) An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes. Front Mol Neurosci 7:72