Histone acetylation and neurite outgrowth in Spinocerebellar ataxia type 1

描述（由申请人提供）：脊髓小脑性共济失调1型（SCA1）是一种遗传性疾病，导致进行性步态不稳定或共济失调。这种疾病是由致病蛋白ataxin-1中谷氨酰胺的扩张引起的。一些趋同的证据表明，扩展的ataxin-1通过引起组蛋白乙酰化增加、募集共抑制因子并最终下调参与维持浦肯野细胞结构和功能的一组基因的转录而对神经元有毒。在我们对ataxin-1的研究中，我们已经确定了它的相互作用蛋白LANP是神经变性的一个极好的候选介质。该蛋白是组蛋白乙酰化和转录的有效抑制剂。在测试LANP在SCA1发病机制中的作用时，我们发现小鼠LANP水平的降低会增加组蛋白乙酰化水平，这与突变ataxin-1诱导的作用相反。此外，我们还发现，消耗神经元细胞系中的LANP促进了神经突的生长，实际上，改善了突变ataxin-1介导的神经突生长不良。这些结果激发了LANP作为SCA1毒性介质在SCA1发病机制中起关键作用的假设。具体来说，我们假设LANP被ataxin-1募集，导致基因启动子的持续低乙酰化，从而导致转录畸变和神经元功能障碍。因此，我们可以预测，降低LANP水平将逆转SCA1中出现的组蛋白低乙酰化，并改善表型。这项探索性/发展性资助计划通过在SCA1小鼠中消耗LANP来验证这一有趣的假设，并测试SCA1表型是否可以如我们在体外工作中提出的那样得到改善。因此，这项研究将为SCA1的一种新的表观遗传致病机制提供见解。此外，这项研究可能会导致基于干扰LANP功能的新疗法。这对于患有这种不治之症的患者来说是一个重要的突破。公共卫生相关性：脊髓小脑性共济失调1型（SCA1）是一种由小脑和脑干变性引起的成人发病神经退行性疾病。在细胞水平上，它的特征是浦肯野细胞和脑干神经元基因表达的改变，这是由突变的ataxin-1引起的，这种遗传疾病中的蛋白质缺陷。我们的研究旨在通过抑制ataxin-1相互作用蛋白LANP的功能来逆转毒性，LANP可能是该疾病转录紊乱的中介。

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.