Non-cell autonomous neurodegeneration in SCA7

描述（由申请人提供）：脊髓小脑共济失调7型（SCA 7）是一种显性遗传形式的橄榄脑桥小脑萎缩，由共济失调蛋白-7基因编码区内的CAG重复扩增引起。尽管确定了与这种疾病相关的精确遗传异常，但共济失调蛋白-7中多聚谷氨酰胺扩增导致选择性神经毒性的机制尚不清楚。在SCA 7（在朊病毒蛋白启动子的控制下表达的多聚谷氨酰胺扩增的共济失调蛋白-7）的转基因小鼠模型中，小脑浦肯野细胞（PC）的变性以非细胞自主的方式发生。SCA 7模型的超微结构分析揭示了PC变性的模式时，PC损伤是由兴奋性毒性损伤。SCA 7小鼠的超微结构评估还揭示了几个小脑元件中的病理学证据，包括攀爬纤维输入的损失和Bergmann神经胶质形态的显著变化。此外，共济失调SCA 7小鼠表现出通常由攀爬纤维和Bergmann神经胶质提供的营养因子的损失。总之，这些观察结果支持SCA 7中PC变性继发于细胞外环境改变的假设。在这个提案中，我们计划解决的问题是如何突变型共济失调蛋白-7改变PC环境，导致PC变性。首先，我们将进行全面的行为，组织学和超微结构分析的自然历史PC变性SCA 7敲入小鼠和小鼠表达的突变蛋白在特定的细胞群体的小脑使用条件灭活策略。第二，将检查细胞外环境的两个具体方面：神经营养因子和神经递质稳态。将进一步表征与SCA 7的转基因和敲入小鼠模型中的疾病表型的发作相关的小脑环境中的特定改变。此外，将开始尝试使SCA 7小鼠的小脑环境正常化的实验，以确定恢复神经营养支持或预防兴奋性毒性是否随后会延迟或预防疾病表型。公共卫生相关性：本提案的首要目标是进一步确定脊髓小脑共济失调7型（SCA 7），遗传性神经退行性疾病的发病机制。长期目标是确定这种毁灭性神经退行性疾病的治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Spinocerebellar Ataxia Type 7 (SCA7) is a dominantly inherited form of olivopontocerebellar atrophy caused by a CAG repeat expansion within the coding region of the gene for the ataxin-7 protein. Despite identification of the precise genetic abnormality associated with this disease, the mechanism by which the polyglutamine expansion in ataxin-7 causes selective neurotoxicity is not known. In a transgenic mouse model of SCA7 (polyglutamine expanded ataxin-7 expressed under the control of the prion protein promoter), degeneration of the cerebellar Purkinje cells (PC's) occurs in a non-cell autonomous fashion. Ultra-structural analysis of this SCA7 model revealed a pattern of PC degeneration observed when PC injury is caused by excitotoxic insult. The ultra-structural evaluation of SCA7 mice also revealed evidence for pathology in several cerebellar elements including loss of climbing fiber input and dramatic changes in the morphology of Bergmann glia. Additionally, ataxic SCA7 mice demonstrate loss of trophic factors normally supplied by climbing fibers and Bergmann glia. Taken together, these observations support the hypothesis that PC degeneration in SCA7 is secondary to an altered extra-cellular environment. In this proposal we plan to address the question of how mutant ataxin-7 alters the PC environment resulting in PC degeneration. First, we will perform comprehensive behavioral, histological and ultra structural analysis of the natural history of PC degeneration in SCA7 knock-in mice and mice expressing the mutant protein in specific cellular populations of the cerebellum using a conditional inactivation strategy. Second, two specific aspects of the extracellular environment will be examined: Neurotrophic factors and Neurotransmitter homeostasis. The specific alterations in the cerebellar environment that are associated with the onset of the disease phenotype in transgenic and knock-in mouse models of SCA7 will be further characterized. Additionally, experiments attempting to normalize the cerebellar environment in SCA7 mice will be initiated in order to determine if restoring neurotrophic support or preventing excitotoxicty will subsequently delay or prevent the disease phenotype. PUBLIC HEALTH RELEVANCE: The overriding objective of this proposal is to further define the pathogenesis of spinocerebellar ataxia type 7 (SCA7), an inherited neurodegenerative disease. The long-term aim is to identify potential targets for therapeutic intervention in this devastating neurodegenerative disease.