Faculty DirectoryRichard I Morimoto
Email Richard Morimoto
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. The 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.
- Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, Neto MF, Brielmann RM, Bessa C, Duarte-Silva S, Miranda A, Oliveira S, Neves-Carvalho A, Bessa J, Summavielle T, Silverman RB, Oliveira P, Morimoto RI, and Maciel P. Brain. 2015 November 1;138(11):3221-3237.
- Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments. Kirstein J, Morito D, Kakihana T, Sugihara M, Minnen A, Hipp MS, Nussbaum-Krammer C, Kasturi P, Hartl FU, Nagata K, and Morimoto RI.EMBO Journal. 2015 September 14;34(18):2334-2349.
- Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction. Labbadia J and Morimoto RI. Molecular Cell. 2015 August 20;59(4):639-650.
- Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nillegoda NB, Kirstein J, Szlachcic A, Berynskyy M, Stank A, Stengel F, Arnsburg K, Gao X, Scior A, Aebersold R, Guilbride DL, Wade RC, Morimoto RI, Mayer MP, and Bukau B. Nature. 2015 August 13;524(7564):247-251.
- Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis. Zhang Y, Zhao KT, Fox SG, Kim J, Kirsch DR, Ferrante RJ,Morimoto RI, and Silverman RB. Journal of Medicinal Chemistry. 2015 August 13;58(15):5942-5949.
- Widespread Proteome Remodeling and Aggregation in Aging C. elegans. Walther DM, Kasturi P, Zheng M, Pinkert S, Vecchi G, Ciryam P, Morimoto RI, Dobson CM, Vendruscolo M, Mann M, and Hartl FU. Cell. 2015 May 7;161(4):919-932.
- Neuronal Serotonin Release Triggers the Heat Shock Response in C. elegans in the Absence of Temperature Increase. Tatum MC, Ooi FK, Chikka MR, Chauve L, Martinez-Velazquez LA, Steinbusch HWM, Morimoto RI, and Prahlad V.Current Biology. 2015 January 19;25(2):163-174.
- Modulation of the Maladaptive Stress Response to Manage Diseases of Protein Folding. Roth DM, Hutt DM, Tong J, Bouchecareilh M, Wang N, Seeley T, Dekkers JF, Beekman JM, Garza D, Drew L, Masliah E, Morimoto RI, and Balch WE.PLoS Biology. 2014 November 18;12(11):e1001998.
- A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease. Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A, Garza D, Vidal M, Ge H, and Morimoto RI. Cell Reports. 2014 November 6;9(3):1135-1150.
- Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis. Trippier PC, Zhao KT, Fox SG, Schiefer IT, Benmohamed R, Moran J, Kirsch DR, Morimoto RI, and Silverman RB. ACS Chemical Neuroscience. 2014 September 17;5(9):823-829.
- Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition. Yu A, Shibata Y, Shah B, Calamini B, Lo DC, and Morimoto RI. PNAS. 2014 April 15;111(15):E1481-E1490.