Histone acetylation and neurite outgrowth in Spinocerebellar ataxia type 1

1 型脊髓小脑共济失调中的组蛋白乙酰化和神经突生长

基本信息

批准号：
7588655
负责人：
Puneet Opal
金额：
$ 19.82万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588655
关键词：
Adult Affect Ataxia Behavioral Binding Biological Assay Brain Stem Breeding Cell Line Cell Nucleus Cellular Structures Cerebellar degeneration Cerebellum Condition Defect Disease Epigenetic Process Equilibrium Event Exploratory/Developmental Grant Gait Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genome Glutamine Hereditary Disease Histone Acetylation Histone Deacetylase Histones In Vitro Inherited Knock-in Mouse Knockout Mice Laboratories Lead Leucine Link Mediating Mediator of activation protein Methods Modeling Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Protein Nuclear Proteins Numbers Pathogenesis Pathology Patients Pharmaceutical Preparations Phenotype Play Population Proteins Public Health Purkinje Cells Recruitment Activity Research Research Design Role Spinocerebellar Ataxias Stretching Testing Therapeutic Toxic effect Type 1 Spinocerebellar Ataxia Work ataxin-1 base cell type disease characteristic gene repression improved inhibitor/antagonist insight mouse model mutant novel polyglutamine promoter retinal rods

项目摘要

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.

描述（由申请人提供）：1型脊髓脑性共济失调（SCA1）是一种遗传性疾病，会导致步态或共济失调的进行性不稳定。该疾病是由于疾病中谷氨酰胺的扩张引起的，引起蛋白质，ataxin-1。几种融合的证据线表明，通过引起组蛋白乙酰化，募集共抑制剂并最终下调与维持Purkinje细胞结构和功能有关的基因子集的转录，对神经元的扩展对神经元有毒。在我们对ataxin-1的研究中，我们将其相互作用的蛋白质LANP确定为神经变性的出色候选介质。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发病机理中的作用时，我们发现小鼠LANP水平降低会增加组蛋白乙酰化的水平，这与突变型ataxin-1诱导的LANP水平相反。此外，我们还发现，神经元细胞线中的LANP耗尽会促进神经突生长，实际上，改善了由突变体ataxin-1介导的可怜的神经突生长。这些结果激发了以下假设，即LANP通过在SCA1中充当毒性中的介体在SCA1发病机理中起关键作用。具体而言，我们假设ataxin-1募集了LANP，以引起基因启动子的持续性低乙酰化，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水平会逆转组蛋白在SCA1中看到的低乙酰化并改善表型。这项探索/发展赠款建议通过在SCA1小鼠中耗尽LANP来检验这一有趣的假设，并测试SCA1表型是否可以按照我们的体外工作所建议的改善。因此，这项研究将提供对SCA1中新型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。对于这种原本无法治愈的疾病的患者来说，这将是一个重要的突破。公共卫生相关性：1型脊髓脑性共济失调（SCA1）是由小脑和脑干变性引起的成人发作神经退行性疾病。在细胞水平上，它的特征是在Purkinje细胞和脑干神经元中因突变蛋白-1带来的脑干神经元的改变，这种遗传疾病中的蛋白质有缺陷。我们的研究旨在通过抑制ataxin-1相互作用的蛋白LANP的功能来逆转毒性，这是该疾病中转录危险的介体。