Richard I. Morimoto
Bill and Gayle Cook Professor
Chaperone Networks and Mechanisms of Protein Conformational Disease
The research in the Morimoto laboratory addresses: (1) How the stress of misfolded proteins leads to the neurodegenerative disorders Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. We are interested in the capacity and specificity of the protein quality control machinery to recognize misfolded and aggregation-prone proteins and the role of molecular chaperones and degradative machines in the triage clearance mechanism. We have established C. elegans transgenic lines expressing polyglutamine proteins (Huntingtin and Ataxin 3), mutant SOD1, tau, and prions to screen for modifiers and suppressors and to establish the basis of neuronal cell-type specificity. We have identified a molecular link between the insulin signaling pathway, accumulation of damaged proteins, and regulation of the heat shock response and chaperones revealing that genes that control longevity also suppress protein misfolding. The identification of the protein quality control proteome thus forms the basis for a new class of therapeutics targeting HSF1 and molecular chaperones for neurodegenerative diseases of aging, (2) Transcriptional regulation of the heat shock response. Role of stress sensors that control HSF1 activation during acute stress and recovery, during aging in response to neurohormonal stress signaling molecules, and as a general regulator of protein homeostasis and suppressor of misfolded proteins, and (3) Systems approach to stress biology. Establishing an organism-wide understanding of chaperone network integration of environmental and physiological stress in C. elegans using genetics, molecular, and informatic tools.
Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX. Lowth BR, Kirstein-Miles J, Saiyed T, Brötz-Oesterhelt H, Morimoto RI, Truscott KN, and Dougan DA. Journal of Structural Biology. 2012 August;179(2):193-201.
Dynamic Imaging by Fluorescence Correlation Spectroscopy Identifies Diverse Populations of Polyglutamine Oligomers Formed in Vivo. Beam M, Silva MC, and Morimoto RI. Journal of Biological Chemistry. 2012 July 27;287(31):26136-26145.
Celastrol Analogues as Inducers of the Heat Shock Response. Design and Synthesis of Affinity Probes for the Identification of Protein Targets. Klaić L, Morimoto RI, and Silverman RB. ACS Chemical Biology. 2012 May 18;7(5):928-937.
Small-molecule proteostasis regulators for protein conformational diseases. Calamini B, Silva MC, Madoux F, Hutt DM, Khanna S, Chalfant MA, Saldanha SA, Hodder P, Tait BD, Garza D, Balch WE, and Morimoto RI. Nature Chemical Biology. 2012 February;8(2):185-196.
Macro-level Modeling of the Response of C. elegans Reproduction to Chronic Heat Stress. McMullen PD, Aprison EZ, Winter PB, Amaral LAN, Morimoto RI, and Ruvinsky I. PLoS Computational Biology. 2012 January 26;8(1):e1002338.
Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells. Zhang W, Benmohamed R, Arvanites AC, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB. Bioorganic & Medicinal Chemistry. 2012 January 15;20(2):1029-1045.
ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis. Chen T, Benmohamed R, Kim J, Smith K, Amante D, Morimoto RI, Kirsch DR, Ferrante RJ, and Silverman RB. Journal of Medicinal Chemistry. 2012 January 12;55(1):515-527.
Remarkable Stereospecific Conjugate Additions to the Hsp90 Inhibitor Celastrol. Klaić L, Trippier PC, Mishra RK, Morimoto RI, and Silverman RB. Journal of the American Chemical Society. 2011 December 14;133(49):19634-19637.
A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network. Silva MC, Fox S, Beam M, Thakkar H, Amaral MD, and Morimoto RI. PLoS Genetics. 2011 December;7(12):e1002438.
Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Prahlad V and Morimoto RI. PNAS. 2011 August 23;108(34):14204-14209.
View all publications by Richard I. Morimoto listed in the National Library of Medicine (PubMed).