Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by inheriting a CAG repeat expansion in the coding region of the ataxin-7 gene, resulting in a polyglutamine (polyQ) expanded mutant protein. SCA7 has features in common with other neurodegenerative disorders caused by polyQ expansion mutations such as Huntington's Disease. One such feature is that degeneration occurs in selectively vulnerable neural populations. In SCA7 the populations that degenerate include Purkinje cells (PCs), Bergmann Glia (BG) and neurons of the inferior olive (IO) which send climbing fiber axons to synapse on PC dendrites. Using animal models of SCA7, we have shown that disease gene expression specifically in BG, PCs and IO neurons influence the SCA7 disease phenotype. Interestingly, using a floxed- polyQ ataxin-7 mouse model of SCA7 we observed that expression of Cre recombinase in all three cell types dramatically delayed symptom onset. Taken together, these findings support the hypothesis that mutant ataxin-7 expression in these three cell types contributes to dysfunctional cellular interactions and is a critical mediator of SCA7 cerebellar degeneration. Unfortunately, the molecular mechanisms responsible for SCA7 pathology in these 3 specific cell types have not yet been determined. We have also observed that suppression of mutant gene expression after symptom onset halts disease progression, but does not reverse pathology in PCs or BG. However, IO inputs to the cerebellum are both decreased and redistributed in SCA7 mice. IO-PC synapse pathology was the only detectable abnormality prevented by suppression of mutant gene expression after symptom onset, suggesting that loss of IO-PC synapses contributes to SCA7 disease progression. Since SCA7 cerebellar pathology involves altered interactions between specific cell types that reside in distinct regions of the CNS, standard approaches to the study of altered gene expression or protein content cannot distinguish between cell type specific changes mechanistically involved in the pathologic process and reactive changes that develop in response to the degeneration of selectively vulnerable cells. To address this issue, we have developed techniques to isolate RNA specifically from the three cellular populations known to impact cerebellar pathology and motor behavior. In this project, we will employ these methods to address the hypothesis that cell type specific changes in both coding and non-coding RNAs lead to the specific pattern of cellular dysfunction observed in the cerebellum of SCA7 mice. We will further identify which RNA changes are reversible following suppression of mutant ataxin-7 expression by inducible Cre- recombinase. These discovery driven experiments are high-risk, but have the potential to yield critical information regarding the molecular mechanisms responsible for selective vulnerability in a polyQ disorder.

Public Health Relevance

Spinocerebellar ataxia type-7 (SCA7) is a fatal inherited neurological disease with no currently available treatment. We have identified specific cellular interactions critical for the maintenance of neurons that degenerate in SCA7 patients. To identify future therapeutic targets for SCA7, this project is aimed at identifying the cell type specific molecular alterations that contribute to disease pathology in a mouse model of SCA7.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-N (03))
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Gwinn, Katrina
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University of Washington
Schools of Medicine
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Jebelli, Joseph; Su, Wei; Hopkins, Stephanie et al. (2015) Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity? Ann N Y Acad Sci 1351:1-10