Understanding the cellular basis of Movement Disorders

脊髓小脑性共济失调1型(SCA1)是九种迟发性神经退行性疾病之一，由 多聚谷氨酰胺(CAG)重复序列的扩展。在SCA1的情况下，致病的谷氨酰胺膨胀影响 Aaxin-1(ATXN1)，一种在转录抑制中起作用的蛋白质。我们和其他人已经在SCA1中发现 遗传小鼠模型，突变的ATXN1早在出生后两周就改变了基因表达，很早就发生了 行为迹象和其他病理事件变得明显。鉴于这些转录的早期性质 我们预测，一些关键基因的表达改变在发病机制中起到了中介作用。在……里面 在验证这一预测的过程中，我们意外地发现，ATXN1直接调节 血管生成和神经营养细胞因子血管内皮生长因子在SCA1中的表达及其异常低水平 老鼠的大脑。根据这一观察结果，我们发现，基因上增加的血管内皮生长因子水平可以缓解 SCA1基因敲除小鼠(SCA1154Q/2Q；Q=谷氨酰胺)的SCA1表型最好 现有的SCA1小鼠模型。我们还在初步的原则证明实验中证明， 血管内皮生长因子的药理作用(通过脑室注射重组血管内皮生长因子)改善小脑 SCA1表型的某些方面，特别是标志性共济失调和小脑树突状病理。有动力 通过这些有希望的结果，我们希望检验两个相关的假设：血管内皮细胞生长因子是一种重要的细胞因子 在SCA1的背景下维持神经血管健康，以及血管内皮生长因子有可能作为治疗 这种原本无法治愈的疾病。我们希望这些研究将提供对 研究SCA1的发病机制，并帮助设计这种疾病的临床试验。一项重要的辅助成果 这些研究将阐明神经系统中血管内皮生长因子的基本生物学，并提供线索 它在其他神经退行性综合征中的作用。

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.