Understanding the cellular basis of Movement Disorders

描述（由申请人提供）：脊髓小脑共济失调1型（SCA 1）是由多聚谷氨酰胺（CAG）重复序列扩增引起的9种迟发性神经退行性疾病之一。在SCA 1的情况下，致病性谷氨酰胺扩增影响共济失调蛋白-1（ATXN 1），一种在转录抑制中起作用的蛋白质。我们和其他人发现，在SCA 1遗传小鼠模型中，突变体ATXN 1早在出生后两周就改变了基因表达，远在行为体征和其他病理事件变得明显之前。鉴于这些转录畸变的早期性质，我们预测，改变表达的几个关键基因在发病机制中起着介导作用。在测试这一预测的过程中，我们意外地发现ATXN 1直接调节血管生成和神经营养细胞因子VEGF的表达，并且其水平在SCA 1小鼠大脑中异常低。根据这一观察结果，我们发现遗传上增加VEGF水平减轻了充分表征的SCA 1敲入小鼠（SCA 1154 Q/2 Q; Q=谷氨酰胺）中的SCA 1表型，SCA 1敲入小鼠是SCA 1的最佳现有小鼠模型。我们还在初步的原理验证实验中证明，VEGF递送的血管内皮生长因子（通过脑室内递送重组VEGF）改善了SCA 1表型的小脑方面，特别是标志性共济失调和小脑树突状病理学。受这些有希望的结果的启发，我们希望测试两个相关的假设：VEGF是在SCA 1的背景下维持神经血管健康的重要细胞因子，并且VEGF有可能作为这种无法治疗的疾病的治疗方法。我们希望这些研究将为SCA 1的发病机制提供机制见解，并帮助设计这种疾病的临床试验。这些研究的一个重要的辅助结果是，它们将阐明VEGF在神经系统中的基本生物学，并为其在其他神经退行性综合征中的作用提供线索。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine late-onset neurodegenerative diseases caused by the expansion of a polyglutamine (CAG) repeat. In the case of SCA1, the pathogenic glutamine expansion affects ataxin-1 (ATXN1), a protein that plays a role in transcriptional repression. We and others have found that in SCA1 genetic mouse models, mutant ATXN1 alters gene expression as early as two weeks after birth, long before behavioral signs and other pathological events become evident. Given the early nature of these transcriptional aberrations, we predicted that altered expression of a few key genes plays a mediatory role in pathogenesis. In the course of testing this prediction, we made the unexpected discovery that ATXN1 directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF and that its levels are abnormally low in the SCA1 mouse brain. Following up on this observation, we discovered that genetically increasing VEGF levels mitigates the SCA1 phenotype in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the best existing mouse model of SCA1. We have also demonstrated in preliminary proof-of-principle experiments that VEGF delivered pharmacologically (by intraventricular delivery of recombinant VEGF) improves the cerebellar aspects of the SCA1 phenotype, specifically the hallmark ataxia and the cerebellar dendritic pathology. Motivated by these promising results, we wish to test two related hypotheses: that VEGF is an important cytokine for maintaining neurovascular health in the context of SCA1, and that VEGF has the potential to serve as therapy for this otherwise untreatable disease. We hope that these studies will provide mechanistic insights into the pathogenesis of SCA1 and also help design clinical trials for this disease. An important ancillary outcome of these studies is that they would shed light on the basic biology of VEGF in the nervous system and provide clues to its role in other neurodegenerative syndromes.