A remarkable feature of the neurodegenerative spinocerebellar ataxias (SCAs) is that glutamine encoding CAG (polyQ) expansions in a diverse set of genes all cause Purkinje cell (PC) and brainstem neuron degeneration. This fact suggests that these genetically distinct polyQ SCAs share key upstream pathogenic events. While PC dysfunction may principally drive motor dysfunction in polyQ SCAs, brainstem dysfunction more closely correlates with premature death. This proposal explores unifying molecular events causing neuronal dysfunction and degeneration in ataxia, with a focus on the polyQ SCAs. In a series of recent publications supported by new data, we identified alterations in potassium (K+) channels as a key feature in several polyQ SCAs. Importantly, in SCA1 transgenic mice, we previously showed that restoring K+ channel expression or function rescued membrane hyperexcitability, improved motor dysfunction and reduced PC degeneration. It is now important to examine the links between K+ channel dysregulation and altered membrane excitability in cerebellar and brainstem neurons, and the relationship of these events to motor dysfunction and neurodegeneration in several polyQ SCAs. In the prior funding period we identified K+ channel dysfunction as the basis of PC spiking abnormalities in models of the polyQ ataxias SCA1, SCA2, SCA3 and SCA7, which together account for the majority of SCAs. To explore shared links between neuronal dysfunction and these functionally diverse polyQ disease proteins, we applied unbiased transcriptomics in models of SCA1, SCA2 and SCA7, and identified a common theme, beginning early in disease: significant reduction in cerebellar transcripts for key ion channels important for K+ channel function. Preliminary data also suggest a reduction in K+ channel transcripts in SCA1 medullary brainstem neurons. The proposal seeks to determine whether altered K+ channel function tied to the biology of diverse polyQ proteins in regulating the transcription and/or stability of ion channel transcripts is a unifying mechanism underlying neuronal dysfunction and degeneration in polyQ SCAs through the following aims:
Aim 1 : Determine whether there is shared potassium channel dysfunction in cerebellar Purkinje cells and brainstem neurons in SCA1.
Aim 2 : Determine whether shared Purkinje cell dysfunction is responsible for motor dysfunction and neurodegeneration in SCA1, SCA2 and SCA7.
Aim 3 : Define the basis for shared reduction in ion channel transcripts in SCA1, SCA2 and SCA7. We anticipate that successful completion of these studies will definitively establish the important role of K+ channel dysfunction in the disease pathogenesis of a wide variety of polyQ ataxias. Further, these studies will demonstrate that abnormal Purkinje neuron spiking causes motor dysfunction in SCAs Lastly, the proposed work will also answer whether K+ channels are compelling therapeutic targets to counter cerebellar and brainstem dysfunction in cerebellar ataxia.

Public Health Relevance

In degenerative cerebellar ataxias, neuronal dysfunction precedes neuronal loss, and is an outstanding target for therapy. In models of SCA1, SCA2 and SCA7, which together represent a significant fraction of the autosomal dominant ataxias, we have identified specific changes in ion channel transcripts that are concurrent with onset of motor dysfunction and prior to degeneration in the cerebellum and brainstem. This proposal seeks to understand the basis for these changes and determine whether motor function and neurodegeneration may be improved through restoring ion channel function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Miller, Daniel L
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Bushart, David D; Chopra, Ravi; Singh, Vikrant et al. (2018) Targeting potassium channels to treat cerebellar ataxia. Ann Clin Transl Neurol 5:297-314
Chopra, Ravi; Wasserman, Aaron H; Pulst, Stefan M et al. (2018) Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia. Hum Mol Genet 27:1396-1410
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