Yale Genetics

Our Department Faculty/Labs Graduate Program Medical Genetics Directory

    Horwich, Arthur

    Professor of Genetics and Pediatrics; Investigator, Howard Hughes Medical Institute

    * A.B. Brown University 1972
    * M.D. Brown University, 1975

    Appointments:

    Sterling Professor of Genetics and Pediatrics; Investigator, Howard Hughes Medical Institute

    Research Interests:

    Chaperones in protein folding
    ALS (Lou Gehrig’s Disease)

    Honors:

    Elected National Academy of Sciences, 2003
    Gairdner International Award, 2004
    Stein and Moore Award of The Protein Society, 2006
    Wiley Prize in Biomedical Sciences, 2007
    Rosenstel Award for Distinguished Work in Basic Medical Sciences 2008
    Institute of Medicine 2008
    Louisa Gross Horwitz Prize 2008

    Current Research:

    Studies of the past decade have shown that many diseases of neurodegeneration are the result of protein misfolding, and we have begun to seek an understanding of the mechanism of such degeneration. We have focused on misfolding caused by mutant forms of the anti-oxidant cytosolic enzyme SOD1 (superoxide dismutase), that produce an inherited form of ALS (Lou Gehrig’s disease), with progressive, fatal motor neuron dysfunction. We are using both C.elegans and mice expressing mutant SOD, and both genetic and biochemical approaches, to investigate how mutant SOD produces motor neuron dysfunction, and are seeking to identify ways to prevent or reverse this. We are also beginning to examine other mouse mutants with inherited ALS, as well as sporadic human ALS, with a view to gaining a broader understanding of disease mechanism.

    The chaperonin ring system carries out an essential step in information transfer from DNA to effector protein, the final step of folding of proteins to their native state. The kinetic assistance provided by these megadalton assemblies is mediated by binding non-native forms in an open ring containing a hydrophobic lining, preventing misfolding and aggregation from occurring, followed by ATP-directed release of bound protein into a now-encapsulated hydrophilic ring where productive folding occurs. Through genetic, biochemical, EM, and X-ray studies, we know a great deal about the states of the chaperonin machine itself (using the bacterial GroEL-GroES as the model system), but the fate of the polypeptide “substrate” is not well understood. For example,

     

    Representative Publications

    Wang, J., Farr, G.W., Hall, D.H., Li, F., Furtak, K., Dreier, L., and Horwich, A.L. (2009), A.L. (2009) An ALS-Linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons C.elegans.  PLoS Genet. 5(1): e1000350. doi:10:371/journal.pgen. 1000350.

    Wang, J., Farr, G.W., Zeiss, C.J., Rodriguez-Gil, D.J., Wilson, J.H., Furtak, K., Rutkowski, D.T., Kaufman, R.J., Ruse, C.I., Yates, J.R. III, Perrin, S., Feany, M.B., and Horwich, A.L. (2009) Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice with ALS.  Proc. Natl. Acad. Sci. USA 106, 1392-1397.

    Apetri, A.C. and Horwich, A.L. (2008) Chaperonin chamber accelerates protein folding through passive action of preventing aggregation.  Proc. Natl. Acad. Sci. USA 105, 17351-17355.

    Elad, N., Farr, G.W., Clare, D.K., Orlova, E.V., Horwich, A.L., and Saibil, H.R. (2007) Topologies of a substrate protein bound to the chaperonin GroEL. Mol Cell 26, 415-426.

    Contact Information:

    Home page of the Horwich Lab
    Our Department Faculty/Labs Graduate Program Medical Genetics Directory