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C. ELEGANS AS A MODEL SYSTEM FOR THE INTEGRATED ANALYSIS OF STRESS RESPONSES AND DISEASES OF PROTEIN MISFOLDING

C. elegans affords an opportunity towards an integrated view of the organismal response to diverse environmental and biochemical stresses, "A SYSTEMS APPROACH TO STRESS BIOLOGY". Our goals are to understand how, when and where stress-signaling pathways converge. For example, if presented with multiple environmental and physiological stress signals, which molecular response is evoked? To accomplish this we will establish genetic and molecular tools to elucidate the heat shock response, osmotic/water stress, expression of mutant and damaged proteins, and oxidative and chemical stresses. This will employ a combination of microarray analysis to identify patterns among the 19,000 C. elegans genes of common and stress-specific genes, statistical and bioinformatic analyses to establish patterns, generation of transgenic animals to identify developmental and tissue-specific expression patterns, and a combination of genome-wide interference RNA and screening for mutants defective in specific stress pathways to establish relationships among stress-induced genes. A major objective is to identify "nodes" of stress regulatory crosstalk between these diverse stress responses and to identify the key cell types that are utilized in the triage mechanism for the organismal response to the environment.

We have established a C. elegans model system for human neurodegenerative diseases by tissue-specific expression of Huntingtin, ataxin-3, polyQ-expansions, superoxide dismutase, tau, sup35, and__-synuclein. For example, expression of these fluorescently-tagged polyglutamine-expansion proteins in neuronal and muscle cells of C. elegans results in the age-dependent appearance of protein aggregates, loss of motility, and selective neuronal toxicity. Protein aggregation and toxicity is suppressed in long-lived age-1 and daf-2 mutants revealing an unexpected link between the genetic pathways involved in longevity and protein homeostasis. We have also observed that overexpression of HSF1 in C. elegans suppresses polyglutamine protein aggregation whereas reduction of HSF1 by interference RNA potentiates aggregate formation. Moreover, reduction in HSF1 activity leads to a progeric phenotype and overexpression of HSF1 increases longevity regulated by the daf-2 (insulin-like) signaling pathway.

The expression of misfolded proteins and appearance of protein aggregates results in a constitutive heat shock response. Consistent with a role of chaperone networks in regulating protein misfolding, overexpression of molecular chaperones (for example S. cerevisiae Hsp104 or Hsp70 and C.e. DnaJ proteins) results in the suppression of the aggregation phenotype. To identify genes that are involved in polyglutamine protein aggregation, we have taken a genome-wide interference RNA screen based on the age-dependent and polyQ-length dependent appearance of protein aggregates (in collaboration with E. Nollen and R. Plasterk, Hubrecht Laboratories). The comprehensive identification of the protein-folding proteome will offer insights to the complexity of genes that collectively control protein homeostasis.

We have also established a genetic approach to investigate the molecular mechanisms regulating the response to osmotic stress and extreme water-loss. A genetic screen for osmotic-stress resistance (Osr) mutants in C. elegans has identified a pioneer gene, OSR-1, that mediates multiple aspects of hyperosmotic stress resistance, including acute dehydration resistance, survival under chronic exposure to hyperosmotic stress and osmotic avoidance behavior. Osr- (rm1) mutants are specifically resistant to osmotic stress as they are sensitive to heat shock, oxidative stress and do not exhibit extended lifespan or dauer constitutive formation. The ability of OSR-1 to regulate survival under chronic hyperosmotic stress, but not acute dehydration resistance or hyperosmotic avoidance, is dependent on the UNC-43/CamKII mediated PMK-1/p38 MAP kinase signaling cascade. We suggest that in C. elegans, OSR-1 regulates multiple responses to hyperosmotic stress via distinct pathways.

References

  1. Gidalevitz, T., T. Krupinski, S. Garcia, and R.I. Morimoto. Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity. PLoS Genet 5(3): e1000399 (2009).
  2. Prahlad, V., T. Cornelius and R.I. Morimoto, . Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons. Science 320: 811-814 (2008).
  3. Prahlad, V., and R.I. Morimoto. Integrating the Stress Response: Lessons for Neurodegenerative Diseases from C. elegans. Trends in Cell Biology 19: 52-61 (2009). [2008 Dec 26 Epub ahead of print]. PMID: 19112021 [PubMed - as supplied by publisher].
  4. Garcia, S. M., M.O. Casanueva, M.C. Silva, M.D. Amaral, and R.I. Morimoto,, Neuronal signaling modulates protein homeostasis in C. elegans postsynaptic muscle cells. Genes and Development 21: 3006-3016 (2007).
  5. 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).
  6. Morimoto, R.I. Stress, Aging and Neurodegenerative Disease. The New England Journal of Medicine 355(21): 2254-2255 (2006).
  7. 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).
  8. 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).
  9. Solomon A, Bandhakavi S, Jabbar S, Shah R, Beitel GJ, Morimoto RI. Caenorhabditis elegans OSR-1 Regulates Behavioral and Physiological Responses to Hyperosmotic Environments. Genetics, 167: 161-170 (2004).
  10. Morley, J.F. and Morimoto, R. Regulation of Longevity in Caenorhabditis elegans by Heat Shock Factor and Molecular Chaperones. Mol Biol Cell. Feb;15:657-64 (2004).
  11. Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI, Plasterk RH. Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A, 101: 6403-6408 (2004).
  12. Morley J.F., Brignull H.R., Weyers J.J., Morimoto R.I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A. (2002).
  13. Shen, X., R.E. Ellis, K. Lee, C.-Y. Liu, K. Yang, A. Solomon, H. Yoshida, R. Morimoto, D.M. Kurnit, K. Mori, and R.J. Kaufman. Complementary Signaling Pathways Regulate the Unfolded Protein Response and Are Required for C. elegans Development. Cell 107: 893-903 (2001).
  14. Satyal SH, Schmidt E, Kitagawa K, Sondheimer N, Lindquist S, Kramer JM, Morimoto RI. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc Natl Acad Sci U S A 23;97(11):5750-5 (2000).
Transcriptional regulation of heat shock response
Roles of Molecular Chaperones in Protein Folding, Trafficking, and Stress Sensors in Cell Growth and Death
All Chaperome Project
Misfolded and aggregation prone proteins in neu
C elegans as a model system for analysis of stress response and diseases of protein misfolding
Small molecule screen for the stress response
Systems Approach to Stress Biology