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.

Finkbeiner, S., A.M. Cuervo, R.I. Morimoto and P.J. Muchowski. Disease-modifiying pathways in neurodegeneration. The Journal of Neuroscience 26(41): 10349-10357 (2006).

Brignull, H.R., J.F. Morley,   S.M. Garcia, and R.I. Morimoto. Modeling Polyglutamine Pathogenesis in C. elegans. Methods in Enzymology 412: 256-282 (2006).  

Morimoto, R.I. Stress, Aging and Neurodegenerative Disease. The New England Journal of Medicine 355(21): 2254-2255 (2006).

Kitamura, A., H. Kubota, C. Pack, G. Matsumoto, S. Hirayama, Y. Takahashi, H. Kimura., M. Kinjo, R. I. Morimoto and K. Nagata. Cytosolic Chaperonin Prevents Polyglutamine Toxicity with Altering the Aggregation State. Nature Cell Biology 8(10):1163-1175 (2006).

Brignull, H., F. Moore, S. Tang, and R. I. Morimoto. Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-Neuronal Caenorhabditis elegans Model. The Journal of Neuroscience 26(29): 7597-7606 (2006).  

Gidalevitz, T., A. Ben-Zvi, K. Ho, H. Brignull, and R. I. Morimoto. Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases . Science 311: 1471-1474 (2006).  

Westerheide, S., T. Kawahara, K. Orton, and R.I. Morimoto. Triptolide, an Inhibitor of the Human Heat Shock Response that Enhances Stress-Induced Cell Death. J. Biol. Chem. 281: 9616-9622 (2006).

Matsumoto, G., S. Kim, and R.I. Morimoto. Huntingtin and mutant SOD1 form aggregate structures with distinct molecular properties in human cells. J Biol Chem. 281: 4477-4485 (2006).

J.F. Morley, H. Brignull, J. Weyers, and R.I. Morimoto. The Threshold for Polyglutamine-Expansion Protein Aggregation and Cellular Toxicity is Dynamic and Influenced by Aging in C. elegans. Proc. Natl. Acad. Science USA 99: 10417-10422 (2002).

R.I. Morimoto. Dynamic Remodeling of Transcription Complexes by Molecular Chaperones. Cell 110: 281-284 (2002).

S. Kim, E.A.A. Nollen, K. Kitagawa, V. Bindokas, and R.I. Morimoto. Polyglutamine Protein Aggregates are Dynamic. Nature Cell Biology 4: 826-831 (2002).

J.F. Morley and R.I. Morimoto. Regulation of Longevity in C. elegans by Heat Shock Factor and Molecular Chaperones. Mol. Biol. Cell 15 : 657-664 (2004).

E.A.A. Nollen, S. Garcia, RG. Van Haaften, S. Kim, R.I. Morimoto, and R.H.A. Plasterek. Genome-wide RNAi Screen Identifies Novel Regulators of Polyglutamine Aggregation. Proc. Natl. Acad. of Science, USA 101: 6403-6408 (2004).

C. Holmberg, K. Staniszewski, K. Mensah, A. Chavez, A. Matouschek, and R.I. Morimoto. Inefficient Degradation of Truncated Polyglutamine Proteins by the Proteasome. EMBO Journal 23: 4307-4318 (2004).

S. Westerheide, J. Bosman, B. Mbadugha, T. Kawahara, G. Matsumoto, W. Gu, S. Kim, J. Devlin, R. Silverman, and R.I. Morimoto. Celastrols as Inducers of the Human Heat Shock Response and Cytoprotection. J. Biol. Chem. 279: 56053-60 (2004).

G.A. Matsumoto, A. Stojanovic, C. Holmberg, S. Kim, and R.I. Morimoto. Structural Properties and Neuronal Toxicity of ALS-Associated SOD1 Aggregates. J. Cell Biology 171: 75-85 (2005).

T. Rieger, R.I. Morimoto, and V. Hatzimanikatis. Mathematical Modeling of the Eukaryotic Heat Shock Response: Dynamics of the Hsp70 Promoter. Biophysical Journal 88 : 1646-1658 (2005).

T. Gidalevitz, A. Ben-Zvi, K. Ho, H. Brignull, and R.I. Morimoto. Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases. Science 311: 1471-1474 (2006).

S. Westerheide, T. Kawahara, K. Orton, and R.I. Morimoto. Triptolide, an Inhibitor of the Human Heat Shock Response that Enhances Stress-Induced Cell Death. J. Biol. Chem. 281: 9616-9622 (2006).

H. Brignull, F. Moore, S. Tang, and R.I. Morimoto. Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-Neuronal C. elegans Model. J. Neuroscience 26: 7597-7606 (2006).

View all publications by publications by Richard I. Morimoto listed in the National Library of Medicine (PubMed).