ERAD genes that suppress neurodegeneration

描述（由申请人提供）：蛋白质稳态是一种动态平衡状态，其中蛋白质产生和正确折叠与蛋白质降解途径平衡，使得蛋白质组能够使细胞正常发挥功能。神经退行性疾病中错误折叠的聚集蛋白质的积累是蛋白质稳态动态中应激的证据，这可能导致细胞功能障碍和死亡。内质网相关降解（ERAD）是应对内质网（ER）中错误折叠蛋白积累的一种机制。ERAD系统由控制底物流入泛素-蛋白酶体途径的正负调节剂的复杂组合组成。一些证据表明ERAD异常是神经退行性疾病模型中神经元功能障碍和死亡的病理生理学贡献者。我假设ERAD途径的选择组分的功能丧失将抑制突变蛋白如超氧化物歧化酶（SOD 1）或43 kDa分子量的TAR DNA结合蛋白（TDP 43）的毒性作用。在具体目标#1中，我将使用C。突变SOD和突变TDP 43毒性的线虫模型，以进行改变毒性的ERAD组分的定向筛选。将使用遗传空值、多个等位基因（如可能）和神经系统特异性RNAi来询问基因。在初步研究中，我们发现两个ERAD基因的无效等位基因抑制突变型SOD或突变型TDP 43表型。最强的毒性抑制剂是rad-23，在具体目标#2中，我们将确定在哺乳动物组织培养模型系统中还原rad 23抑制突变SOD和突变TDP 43毒性的分子机制。我将测试的假设，即损失的rad 23 A加速降解的错误折叠的蛋白质。这些研究将共同确定新的干预目标和途径，以对抗神经退行性疾病。

DESCRIPTION (provided by applicant): Protein homeostasis is a state of dynamic equilibrium in which protein production and proper folding is balanced against the protein degradation pathways such that the proteome enables cells to function normally. The accumulation of misfolded, aggregated proteins in neurodegenerative diseases is evidence for stress in the protein homeostasis dynamic and this can lead to cell dysfunction and death. One mechanism for coping with the accumulation of misfolded proteins in the endoplasmic reticulum (ER) is ER associated degradation (ERAD). The ERAD system is composed of an intricate assembly of positive and negative regulators that control the flow of substrates into the ubiquitin-proteosome pathway. Several lines of evidence implicate abnormalities in ERAD as pathophysiological contributors to neuronal dysfunction and death in models of neurodegenerative disease. I hypothesize that loss of function of select components of the ERAD pathway will suppress the toxic actions of mutant proteins such as superoxide dismutase (SOD1) or TAR DNA binding protein of 43 kDa molecular weight (TDP43). In specific aim #1, I will use C. elegans models of mutant SOD and mutant TDP43 toxicity to undertake a directed screen of ERAD components that modify toxicity. Genes will be interrogated using genetic nulls, multiple alleles when possible and nervous system specific RNAi. In Preliminary studies we have found that null alleles of two ERAD genes suppress mutant SOD or mutant TDP43 phenotypes. The strongest suppressor of toxicity was rad-23 and in specific aim #2 we will determine the molecular mechanism by which reduction of rad23 suppresses the toxicity of mutant SOD and mutant TDP43 in a mammalian tissue culture model system. I will test the hypothesis that loss of rad23A accelerates the degradation of misfolded proteins. Together these studies will identify new targets and pathways for intervention to combat neurodegenerative disease.