Modulating aggrephagy to modify Huntington's disease

调节聚合吞噬以改变亨廷顿病

• 批准号: 8842210
• 负责人: Ai Yamamoto
• 金额: $ 38.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842210
• 关键词: Adult; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Appearance; Autophagocytosis; Autophagosome; Degradation Pathway; Deposition; Disease; Event; Goals; Huntington Disease; Inherited; Knock-out; Lead; Length; Link; Lysosomes; Mediating; Membrane; Mitochondria; Modeling; Neurodegenerative Disorders; Neurons; Outcome Study; Parkinson Disease; Pathogenesis; Pathway interactions; Persons; Phenotype; Prevention; Process; Proteins; Research; Role; Series; Starvation; Structure; Symptoms; System; Tertiary Protein Structure; Therapeutic; Transgenic Organisms; Validation; effective therapy; human Huntingtin protein; insight; mouse model; mutant; new therapeutic target; overexpression; polyglutamine; prevent; protein aggregate; protein aggregation; protein degradation; response; success; trafficking

DESCRIPTION (provided by applicant): Over the last decade, studies have revealed that diminishing mutant huntingtin levels in mouse models of Huntington's disease (HD) leads to the amelioration of pre-existing symptoms, raising the tantalizing possibility for a cure. One of the primary events that accompany symptomatic reversal is the concomitant clearance of the aggregated mutant protein. Despite the intense debate that surrounds the role of protein aggregation in the pathogenesis of HD, a great amount of effort has been put forward to inhibit or disaggregate these proteinaceous intracellular deposits, with limited success. More recently, efforts to drive the turnover of these structures have been proposed, with some promise. One difficulty with these studies has been the inability to target protein degradation pathways in such a way to either enhance or impede the selective elimination of the aggregates, often leading to unwanted, nonspecific consequences that obscure the interpretation of the studies outcome. Recent studies have emerged demonstrating that the protein degradation pathway macroautophagy is capable of the selective degradation of various cargo including ubiquitinated protein aggregates. We have identified the Autophagy linked FYVE domain protein (Alfy) as essential to this process: Importantly not only does depletion of Alfy inhibit the macroautophagic clearance of aggregated mutant htt, but it does so without inhibiting basal and starvation-mediated macroautophagy. Moreover, over-expression of Alfy in neurons led to fewer mutant huntingtin inclusions. In response to the PAS-10-183 Validation of Novel Therapeutic Targets for Huntington's disease, we propose to use Alfy to genetically determine whether the clearance of aggregated mutant huntingtin represents a valid therapeutic approach in HD.

描述（由申请人提供）：在过去的十年中，研究表明，亨廷顿氏病小鼠模型（HD）中突变体亨廷顿素水平降低导致既有症状的改善，从而增加了治愈的可能性。伴随有症状的逆转的主要事件之一是聚合突变蛋白的伴随清除率。尽管围绕蛋白质聚集在HD发病机理中的作用的激烈争论，但已经提出了大量努力来抑制或分类这些蛋白质内细胞内沉积物，并取得有限的成功。最近，已经提出了推动这些结构营业额的努力，并有所承诺。这些研究的一个困难是无法以这种方式靶向蛋白质降解途径，以增强或阻碍选择性消除聚集体的选择性，通常会导致不需要的，非特异性的后果，从而掩盖了研究结果的解释。最近的研究表明，蛋白质降解途径大量噬菌能够选择性降解各种货物，包括泛素化的蛋白质聚集体。我们已经确定自噬连接的FYVE结构域蛋白（ALFY）对于这一过程至关重要：重要的是，ARFY的耗尽不仅会抑制聚集的突变体HTT的大噬菌学清除率，而且它在不抑制基础和饥饿介导的微生物嗜碱性噬菌体的情况下确实如此。此外，神经元中Alfy的过表达导致亨廷顿蛋白的突变体较少。为了响应PAS-10-183对亨廷顿氏病的新型治疗靶标的验证，我们建议使用ALFY来遗传确定综合突变体亨廷顿蛋白的清除是否代表了HD中的有效治疗方法。