Suppression of the heat shock response in aging and neurodegeneration

描述(申请人提供)：几种保护机制已经在细胞中进化，以处理错误折叠或突变多肽的积累。例如，分子伴侣专门用于防止异常多肽的聚集和促进其复性。在异常蛋白质急剧积累的情况下，当对伴侣的需求增加时，热休克转录因子HSF1被激活，并促进分子伴侣的转录。然而，令人惊讶的是，在许多神经退行性疾病中，包括亨廷顿病(Huntington‘s，HD)或帕金森病(Parkinson’s，PD)，尽管异常病理性多肽堆积，但伴侣蛋白水平降低，对应激反应的伴侣蛋白诱导受到抑制。这种对伴侣诱导的抑制会降低细胞处理错误折叠的病理蛋白的能力，这将刺激一个促进毒性和神经退化的正反馈回路。热休克反应(HSR)在衰老生物体和衰老细胞中也被强烈下调。这种年龄介导的抑制降低了伴侣系统的有效性，这可能会导致迟发性疾病中的神经退化。我们发现，包括P53-p21信号通路和蛋白激酶CDK5在内的信号模块介导了对衰老细胞热休克反应的抑制。这项建议的目标是了解导致细胞和线虫衰老和神经退化模型中HSR抑制的信号事件序列。具体地说，我们将(1)在HD细胞模型中确定P53在抑制HSR中的作用；(2)在细胞衰老和HD细胞模型中建立CDK5在抑制HSR中的作用；以及(3)在线虫衰老和HD模型中建立P53通路和CDK5在抑制HSR中的作用。这项研究还将探讨抑制CDK5是否可以增强HSR并改善衰老和HD模型的生存能力。许多与衰老相关的神经退行性疾病是由异常蛋白质的积累引起的。一种特殊的分子伴侣机制已经进化出来，以防止聚集，并促进这些异常物种的折叠和降解。然而，伴侣机制在衰老和疾病中下调，这项工作将发现导致伴侣机制抑制的信号事件。

DESCRIPTION (provided by applicant): Several protective mechanisms have evolved in cells to handle accumulation of misfolded or mutant polypeptides. For example, molecular chaperones specifically serve to prevent aggregation and promote refolding of abnormal polypeptides. In conditions of acute accumulation of abnormal proteins when the demand for chaperones increases, a heat shock transcription factor, Hsf1, gets activated and promotes transcription of molecular chaperones. However, surprisingly, in many neurodegenerative disorders, including Huntington's (HD) or Parkinson's (PD) diseases, in spite of a build-up of abnormal pathological polypeptides, the levels of chaperones are reduced and induction of chaperones in response to stress is suppressed. Such suppression of the chaperone induction can reduce the ability of cells to handle misfolded pathological proteins, which would stimulate a positive feedback loop promoting toxicity and neurodegeneration. The heat shock response (HSR) is also strongly downregulated in aged organisms and senescent cells. This age-mediated suppression reduces the efficacy of the chaperone system, which could contribute to neurodegeneration in the late-onset disorders. We have found that signaling modules, including the p53-p21 signaling pathway and the protein kinase Cdk5 mediate suppression of the heat shock response in senescent cells. The goal of this proposal is to understand the sequence of signaling events that lead to suppression of the HSR in the cellular and C.elegans models of aging and neurodegeneration. Specifically, we will (1) establish the role of p53 in suppression of the HSR in cellular models of HD; (2) establish the role of Cdk5 in suppression of the HSR in cell senescence and cellular models of HD, and (3) establish the role of the p53 pathway and Cdk5 in suppression of the HSR in C.elegans models of aging and HD. This research will also address whether inhibition of Cdk5 can enhance the HSR and improve viability in aging and HD models. Many neurodegenerative disorders associated with aging are caused by accumulation of abnormal proteins. A special machinery of molecular chaperones has evolved to prevent aggregation and promote refolding and degradation of these abnormal species. The chaperone machinery however is downregulated in aging and disease, and this work will uncover signaling events that lead to suppression of the chaperone machinery.