Polyglutamine Expansion Length Dependent Pathology

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 DESCRIPTION (provided by applicant): There are at least nine inherited neurodegenerative disorders caused by the expansion of a polyglutamine (polyQ) domain in the respective disease proteins, including Huntington's disease (HD) and several spinocerebellar ataxia (SCA) disorders. Although all polyQ disease proteins are expressed throughout the brain and body, they selectively affect neurons and a few other types of cells in an age-dependent manner. In addition, different polyQ lengths cause different symptoms in juvenile and adult patients, indicating that polyQ repeats can induce cell-type specific and age-dependent pathology. Understanding how the expanded polyQ-containing proteins mediate the selective pathology is critical if we are to develop effective therapeutic strategies for treating these polyQ diseases. Although we know that protein context modulates the toxicity of polyQ expansion seen in polyQ diseases, the mechanism behind the repeat length dependent selective pathology remains unknown Protein context confers the selectivity of polyQ toxicity because it determines protein-protein interactions, half-life and stability, and subcellular localization. However, the length of polyQ also can modulate the selectivity of polyQ protein toxicity. The strong evidence is that in HD, polyQ repeats larger than 60 glutamines cause juvenile cases that show symptoms different from those in adult HD patients. Similarly, expansion of the polyQ tract (>42 glutamines) in TBP induces clinical symptoms in SCA17 patients. However, when polyQ repeats are more than 63Q, mutant TBP causes juvenile-onset SCA-17 cases with retarded growth, progressive clinical symptoms, and early death as well as marked muscle weakness, which are different from those in adult-onset SCA17 patients. We hypothesize that polyQ repeat length determines differential pathology via its effect on protein interactions in cell- or tissue-dependet manner. To test this hypothesis, we will use SCA17 mice that express mutant TBP containing different polyQ repeats in neuronal or muscles cells. SCA-17 is an excellent model for us to investigate the mechanism behind the differential pathology in polyQ disease as the function of TBP is well characterized. Specifically, in Aim 1 we will characterize the cell type-dependent pathology in SCA17 knock-in mice. In Aim 2 we will use SCA17 knock-in mice and AAV vectors expressing TBP containing different polyQ repeats to investigate polyQ repeat length-dependent pathology in neuronal and muscle cells. In Aim 3 we will explore the mechanisms underlying specific effects of polyQ lengths by examining the effects of different polyQ repeat lengths on the interactions of mutant TBP with transcription factors in neuronal and muscle cells. These studies will provide new insight into the differential pathology and phenotypes caused by different polyQ repeat lengths in juvenile and adult polyQ diseases.