Identifying symptomatic and neuroprotective strategies for cereballar ataxia

确定小脑共济失调的症状和神经保护策略

• 批准号: 10605349
• 负责人: Vikram Govindaraju Shakkottai
• 金额: $ 50.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605349
• 关键词: Address; Ataxia; Bacterial Artificial Chromosomes; Biology; Brain; Brain Stem; Cause of Death; Cell physiology; Cerebellar Ataxia; Cerebellum; Cessation of life; Data; Disease; Electrophysiology (science); Event; Functional disorder; Funding; Genes; Genetic Transcription; Genetic study; Glutamine; Immunoprecipitation; Impairment; Inferior; Ion Channel; Knock-in; Knock-in Mouse; LY6E gene; Link; MJD1 protein; Mediating; Membrane; Modeling; Molecular; Motor; Nerve Degeneration; Neuronal Dysfunction; Neurons; Olives - dietary; Pathogenesis; Pathogenicity; Pathway interactions; Physiology; Play; Potassium Channel; Proteins; Publications; Purkinje Cells; RNA; RNA Stability; Role; Series; Slice; Spinocerebellar Ataxias; Transcript; Transgenic Mice; Transgenic Organisms; Viral; Work; autosome; chromatin immunoprecipitation; improved; in vivo; insight; motor disorder; mouse genetics; mouse model; mutant; neuron loss; neuroprotection; polyglutamine; premature; targeted treatment; therapeutic target; transcriptomics

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.

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.