Genetic mechanism of spinocerebellar ataxia type 10

脊髓小脑共济失调10型的遗传机制

• 批准号: 7195713
• 负责人: MICHAEL D TOPAL
• 金额: $ 7.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195713
• 关键词: Affect; Binding Proteins; Biological; Brain; Cell Death; Cell Extracts; Cell Nucleus; Class; Contracts; Data; Disease; Electron Microscopy; Environment; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hela Cells; Heterogeneous Nuclear RNA; Human; Human Genome; Huntington Disease; Inherited; Introns; Investigation; Knowledge; Localized; Mass Spectrum Analysis; Molecular; Myotonic Dystrophy; Nerve Degeneration; Neuromuscular Diseases; Neurons; Nuclear; Nucleic Acids; Pathway interactions; Protein Splicing; Proteins; Purpose; RNA; RNA Splicing; Recording of previous events; Research; Resource Sharing; Resources; Spinocerebellar Ataxias; Study Section; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Untranslated Regions; Work; base; expectation; gain of function; innovation; interest; knock-down; loss of function; mRNA Precursor; member; novel therapeutics; size

DESCRIPTION (provided by applicant): Repeat expansions in the human genome are responsible for more than thirty neurodegenerative and neuromuscular diseases, including the dominantly inherited diseases myotonic dystrophy types 1 and 2 (DM1 and DM2), Huntington's disease, and the spinocerebellar ataxias (SCAs). The repeats associated with DM1, d(CTG)n, and DM2, d(CCTG)n, lie in untranslated regions of their host gene. The repeat expansions reach dramatic sizes of thousands of repeats and generate gain-of-function "toxic" CUG repeat RNAs that accumulate in nuclear foci and interact with CUG repeat binding proteins involved in control of tissue-specific pre-mRNA splicing. Similarly, the SCA type 10 (SCA10) d(ATTCT)n repeat expansions occur in an untranslated intron and reach dramatic sizes. This, plus our preliminary results, suggests that dominantly inherited SCA10 disease, like DM1 and DM2, may be a toxic RNA disease. In contrast, knock down of SCA10 gene expression in neurons increases cell death, suggesting that SCA10 may be a loss-of-function disease. Thus, it is entirely unclear how the expanded ATTCT repeat leads to SCA10 disease. It is unclear that the AUUCU-repeat-containing intronic RNA is stable after splicing, and the possibility of an AUUCU binding protein is provocative and could uncover a new class of proteins that regulate pre-mRNA splicing. Lack of understanding of how the d(ATTCT)n repeat expansion alters tissue-specific gene expression is a critical problem, because until this information becomes available, it will not be possible to develop new therapeutic strategies. The long-term goal of this research is to determine the biological pathways impacted by the ATTCT repeat expansion to cause SCA10 disease. The central hypothesis for the proposed research is that SCA10 disease is manifested by a toxic RNA effect that interferes with correct splicing of brain-specific pre-mRNAs. The central hypothesis will be tested by pursuing the following specific aims: 1) localize the RNAs transcribed from SCA10 d(ATTCT)n repeat expansions; 2) identify proteins that interact with the expanded SCA10 RNA.

描述(申请人提供)：人类基因组的重复扩张导致了30多种神经退行性和神经肌肉疾病，包括主要的遗传性疾病强直性肌营养不良1型和2型(DM1和DM2)，亨廷顿病，以及脊髓小脑性共济失调(SCA)。与DM1，d(CTG)n和DM2，d(CCTG)n相关的重复序列位于宿主基因的非翻译区。重复序列的扩展达到数千个重复序列的戏剧性大小，并产生功能增强的“有毒”CUG重复RNA，这些RNA积累在核病灶中，并与参与控制组织特异性前-mRNA剪接的CUG重复结合蛋白相互作用。同样，SCA类型10(SCA10)d(ATTCT)n重复扩展发生在未翻译的内含子中，并达到惊人的大小。这一点，加上我们的初步结果，表明主要遗传的SCA10疾病，如DM1和DM2，可能是一种毒性RNA疾病。相反，SCA10基因在神经元中的表达下调会增加细胞死亡，这表明SCA10可能是一种功能丧失的疾病。因此，目前还完全不清楚ATTCT重复序列是如何导致SCA10疾病的。目前尚不清楚含有AUUCU重复序列的内含子RNA在剪接后是否稳定，AUUCU结合蛋白的可能性是挑衅性的，可能会发现一类新的蛋白质来调节前mRNA的剪接。缺乏对d(ATTCT)n重复扩增如何改变组织特异性基因表达的了解是一个关键问题，因为在获得这些信息之前，不可能开发新的治疗策略。这项研究的长期目标是确定ATTCT重复扩增影响导致SCA10疾病的生物学途径。这项拟议研究的中心假设是，SCA10疾病是由一种有毒的RNA效应表现出来的，这种效应干扰了大脑特定前-mRNAs的正确剪接。中心假设将通过追求以下特定目标来验证：1)定位从SCA10 d(ATTCT)n重复扩展转录的RNA；2)识别与扩展的SCA10 RNA相互作用的蛋白质。