Histone acetylation and neurite outgrowth in Spinocerebellar ataxia type 1

描述（由申请人提供）：脊髓小脑共济失调1型（SCA 1）是一种遗传性疾病，可导致进行性步态不稳或共济失调。这种疾病是由引起疾病的蛋白质ataxin-1中的一段谷氨酰胺的扩张引起的。几个趋同的证据表明，扩大ataxin-1是有毒的神经元，引起增加组蛋白乙酰化，招募共阻遏物，并最终下调转录的一个子集的基因参与维持浦肯野细胞的结构和功能。在我们的研究ataxin-1，我们已经确定其相互作用蛋白LANP作为一个很好的候选调解人的神经退行性变。这种蛋白质是组蛋白乙酰化和转录的有效抑制剂。在测试LANP在SCA 1发病机制中的作用时，我们发现小鼠中LANP水平降低会增加组蛋白乙酰化水平，这与突变型共济失调蛋白-1诱导的作用相反。此外，我们还发现，在神经元细胞系中消耗LANP促进神经突生长，事实上，改善突变型共济失调蛋白-1介导的神经突生长不良。这些结果激发了这样的假设，即LANP通过在SCA 1中充当毒性的介体而在SCA 1发病机制中起关键作用。具体来说，我们假设LANP是由共济失调蛋白-1引起持续的低乙酰化基因的启动子，导致转录畸变和神经元功能障碍。因此，我们预测降低LANP水平将逆转SCA 1中观察到的组蛋白低乙酰化并改善表型。这项探索性/发展性资助计划通过消耗SCA 1小鼠中的LANP来测试这一有趣的假设，并测试SCA 1表型是否可以像我们的体外工作所建议的那样得到改善。因此，这项研究将提供一个新的SCA 1表观遗传致病机制的见解。此外，这项研究可能会导致基于干扰LANP功能的新疗法。这将是一个重要的突破，为病人与这种其他不治之症。公共卫生相关性：脊髓小脑性共济失调1型（SCA 1）是一种由小脑和脑干变性引起的成人神经退行性疾病。在细胞水平上，它的特征是由突变型共济失调蛋白-1（这种遗传性疾病中的蛋白质缺陷）引起的浦肯野细胞和脑干神经元中基因表达的改变。我们的研究旨在试图通过抑制共济失调蛋白-1相互作用蛋白LANP的功能来逆转毒性，LANP是这种疾病中转录紊乱的可能介质。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an inherited disease that causes progressive instability of gait or ataxia. This disease is caused by an expansion of a stretch of glutamines in the disease causing protein, ataxin-1. Several converging lines of evidence suggest that expanded ataxin-1 is toxic to neurons by causing increased histone acetylation, recruiting co-repressors and ultimately downregulating the transcription of a subset of genes involved in maintaining Purkinje cell structure and function. In our studies on ataxin-1, we have identified its interacting protein LANP as an excellent candidate mediator of neurodegeneration. This protein is a potent inhibitor of histone acetylation and transcription. In testing for a role of LANP in SCA1 pathogenesis, we have found that decreasing LANP levels in mice increases the levels of histone acetylation, an effect opposite to that induced by mutant ataxin-1. Moreover, we have also discovered that depleting LANP in neuronal cell-lines promotes neurite outgrowth, indeed, ameliorating the poor neurite outgrowth mediated by mutant ataxin-1. These results inspire the hypothesis that LANP plays a key role in SCA1 pathogenesis by serving as a mediator of toxicity in SCA1. Specifically, we postulate that LANP is recruited by ataxin-1 to cause persistent hypoacetylation at promoters of genes resulting in transcriptional aberrations and neuronal dysfunction. We would therefore predict that reducing LANP levels would reverse histone hypoacetylation seen in SCA1 and improve the phenotype. This exploratory/developmental grant proposes to test this intriguing hypothesis by depleting LANP in SCA1 mice and testing whether the SCA1 phenotype can be ameliorated as suggested by our in vitro work. This study would thus provide insights into a novel epigenetic pathogenic mechanism in SCA1. In addition, this study could lead to new therapies based on interfering with LANP function. This would represent an important breakthrough for patients with this otherwise incurable disease. PUBLIC HEALTH RELEVANCE: Spinocerebellar Ataxia Type 1 (SCA1) is an adult onset neurodegenerative disease caused by degeneration of the cerebellum and the brainstem. At a cellular level, it is characterized by alterations in gene expression in Purkinje cells and brainstem neurons brought about by mutant ataxin-1, the protein defective in this genetic disease. Our studies are aimed at attempting to reverse toxicity by inhibiting the functions of the ataxin-1 interacting protein LANP, a likely mediator of transcriptional derangements in this disease.