[Seminar] Regulation of the Heat Shock Response and Proteostasis Networks in Aging and Disease by Dr. Richard Morimoto

Abstract

The heat shock response (HSR) has been an exceptional tool for biology that has uncovered fundamentals of cell and molecular biology and the basis of cell stress resilience, adaptation and survival mechanisms. From the simple use of elevated temperature stress, the field has established the mechanisms by which temperature reprograms transcription and translation, the logic of protein quality control systems and the role of the proteostasis network (PN) to determine cellular health and lifespan.  To understand the biology of organismal proteostasis, we have used C. elegans to examine the properties of the PN in different tissues during development through adulthood into aging.  These transitions impose a tremendous strain on the quality control machinery to maintain the functional health of the proteome.  In early development, heat shock transcription factor, HSF-1, is essential and together with the cell cycle factor, E2F, co-regulates a subset of chaperone and PN genes involved in anabolic growth.  HSF-1 binding is also involved in the suppression of protein degradation pathways in early development.  These processes are however distinct from the transcriptional program of the heat shock response which is essential to survive exposure to diverse cell stress conditions.  As egg-laying commences, the HSR in somatic tissues is repressed by epigenetic reprogramming of chromatin with a decline in the jumonji demethylase and increased H3K27me3 marks in the chromatin of cell stress response gene promoters.  The inhibitory signal emanates from germ line stem cells and can be reversed by blocking the germ line signal, by overexpression of the jumonji demethylase, or by mild mitochondrial stress to prevent proteostasis collapse in early adulthood. These observations lead us to propose that failure of the HSR in aging is genetically programmed, perhaps to ensure that germline survival coincides with the decline of the soma. The timing of proteostasis collapse ensures that the free-living adult animal post-fecundity lacking stress resilience survives poorly and thus does not compete for limiting resources.  We propose that such a genetically regulated switch of the HSR during early aging is the basis for increased risk for misfolding and aggregation as occurs in neurodegenerative diseases and other protein conformational diseases.

Biography

Rick Morimoto is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research in the Department of Molecular Biosciences at Northwestern University. He holds a B.S. from the University of Illinois, a Ph.D. in Molecular Biology from The University of Chicago, and was a postdoctoral fellow at Harvard University.  

Dr. Morimoto has been on the faculty in the Department of Molecular Biosciences since 1982.  The biomedical research carried out in his laboratory has been continuously supported by research grants from the National Institute of General Medical Sciences, National Institute on Aging, National Institute of Neurological Diseases and Stroke, National Institutes of Mental Health, American Cancer Society, Huntington Disease Society of America, the Hereditary Disease Foundation, the Department of Defense, International Human Frontier Science Program Organization, the ALS Association and the Ellison Medical Foundation.  His research addresses the regulation of the heat shock stress response and the function of molecular chaperones that are central to diverse protein conformational diseases including Huntington's disease, Parkinson's disease, ALS, and Alzheimer's disease.  His current research is to understand how animals sense and respond to physiologic and environmental stress through the activation of genetic pathways that integrate stress responses with molecular and cellular responses that determine cell growth and cell death.  The stress of misfolded and damaged proteins influences neuronal function and lifespan at the level of the organism.  These studies provide a molecular basis to elucidate the underlying mechanisms of aging and age-associated neurodegenerative disease. 

Dr. Morimoto's laboratory has published over 280 papers including three monographs and three books on the Heat Shock Response and Molecular Chaperones from Cold Spring Harbor Press. In 2008, he co-founded a Biotech company, Proteostasis Therapeutics, Inc. in Cambridge, MA with the goal to discover small molecule therapeutics for diseases of protein conformation such as Alzheimer’s disease, Parkinson's disease, Huntington’s disease, cystic fibrosis, cancer, and type II diabetes.