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.
| Kim, Geunwon; Meriin, Anatoli B; Gabai, Vladimir L et al. (2012) The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell 11:617-27 |
