ginny-harris@uiowa.edu
Mentor: Pedro Gonzalez-Alegre, M.D.
Lab Room: 3111 MERF
Lab Phone: 319-335-9178

Role of Protein Context in the Pathogenesis of Spinocerebellar Ataxia, Type 3

The hereditary ataxia Spinocerebellar ataxia type 3 (SCA3, Machado-Joseph Disease, MJD) is a form of polyglutamine disease. This important class of at least 9 neurodegenerative disorders is characterized by expanded polyglutamine tracts that are thought to misfold and confer a toxic property on the disease proteins. Despite a common molecular insult, the clinical manifestations of individual polyglutamine diseases vary significantly. This difference is likely due to the context of the polyglutamine expansion within its unique disease protein. In order to understand the disease process in SCA3, the focus on my research will explore both general features of polyglutamine toxicity and specific properties of ataxin-3, the disease protein in SCA3. Ataxin-3 is a unique de-ubiquitinating enzyme. It consists of a "Josephin" cysteine protease domain, a polyglutamine repeat, and two to three ubiquitin interacting motifs (UIMs). The variation in UIM number is due to alternative splicing; however, the functional significance of this is not yet known. Orthologs of ataxin-3 exist in many species, including Mus musculus Atxn3, which is highly conserved, particularly in exons encoding the N-terminus. Although several transgenic mouse models currently exist, none is expressed under the endogenous murine Atxn3 promoter in the normal genomic context. I am currently interested in exploring the developmental regulation and functional significance of ataxin-3 splice variation. I am also developing a knock-in of expanded polyglutamine in the Atxn3 gene, a genetically precise model of disease that will be well suited for in vivo RNAi knockdown, pharmacological intervention, endogenous splice variant analysis, and genomic instability studies. Both aims will enhance our understanding of the influences of protein context on polyglutamine toxicity.

Publications:

Harris GM, Dodelzon K, Gong L, Gonzalez-Alegre P, Paulson HL. Splice isoforms of the polyglutamine disease protein ataxin-3 exhibit similar enzymatic yet different aggregation properties. PLoS One. 2010 Oct 27;5(10):e13695. PubMed PMID: 21060878; PubMed Central PMCID: PMC2965175

Abstracts:

Harris GM, Dodelzon K, Paulson HL. Alternative splicing of Ataxin-3, a polyglutamine (polyQ) disease protein. FASEB Journal 21 (6): A1274-A1274, 2007.