Richard I. Morimoto Cell stress responses, molecular chaperones, protein conformational disease

Research Interests

Protein quality control is an essential process for all cells for the timely and efficient synthesis, folding, assembly and degradation of all proteins. This is achieved by the proteostasis network (PN) of translation factors, molecular chaperones, the autophagy-lysosomal pathway and the ubiquitin-proteasome system. While robust in youth, the PN is compromised in cell stress and aging, which is the primary contributor to hundreds of diseases of protein conformation including cancer, metabolic and muscle wasting diseases, Alzheimer’s disease, Frontal Temporal Dementia, Parkinson’s Disease, ALS and Huntington’s Diseases.  Our studies employ two model systems; C. elegans for discovery science on the molecular processes that control proteome quality, stability and functional health in aging, and patient derived induced neurons for Tauopathies and Alzheimer’s Disease to monitor the PN and to identify small molecules that restore proteostasis, cell-protective mechanisms and cellular health in aging and diseases. Our current projects are: to understand how intertissue communication coordinates cell stress responses and organismal cellular health, to understand the mechanisms and timing of proteostasis collapse in aging, to establish the relationship between proteostasis collapse and other events in aging, to establish the threshold for tolerated protein misfolding stress and the effects of aging on this process, and to identify small molecule therapeutic strategies targeting proteostasis mechanisms to prevent protein misfolding.

Selected Publications

Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Capano LS, Sato C, Ficulle E, Yu A, Horie K, Kwon J-S, Burbach KF, Barthélemy NR, Fox SG, Karch CM, Bateman RJ, Houlden H, Morimoto RI, Holtzman DM, Duff KE, and Yoo AS. Cell Stem Cell. 2022 June 2;29(6):918-932.E8.

Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans. Sinnige T, Meisl G, Michaels TCT, Vendruscolo M, Knowles TPJ, and Morimoto RI. PNAS. 2021 March 16;118(11):e2021888118.

Embryo integrity regulates maternal proteostasis and stress resilience. Sala AJ, Bott LC, Brielmann RM, and Morimoto RI. Genes & Development. 2020 May 1;34(9-10):678-687. 

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging. Labbadia J, Brielmann RM, Neto MF, Lin Y-F, Haynes CM, and Morimoto RI. Cell Reports. 2017 November 7;21(6):1481-1494.

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.

Widespread Proteome Remodeling and Aggregation in Aging C. elegansWalther 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.

Regulation of Organismal Proteostasis by Transcellular Chaperone Signaling. van Oosten-Hawle P, Porter RS, and Morimoto RI. Cell. 2013 June 6;153(6):1366-1378. 

View all publications by Richard I. Morimoto listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.