Biomedical Sciences Graduate Program | University of California, San Francisco

Paul Muchowski, PhD
Molecular mechanisms that underlie neurodegenerative disorders

Selected Publications | Complete Publications

phone	(415) 734-2515
email	pmuchowski@gladstone.ucsf.edu
additional websites	Lab website
secondary research affiliation	Human Genetics

The major research goal of our laboratory is to understand the molecular mechanisms that underlie neurodegenerative disorders associated with protein misfolding and aggregation, focusing on Alzheimer's disease, Huntington's disease and Parkinson's disease.

We utilize a broad array of tools and methods in our studies, including structural analyses of protein aggregation reactions in vitro, yeast genetic screens to identify proteins that modulate aggregation and toxicity of disease-causing proteins, and molecular genetic approaches in neuronal and animal models of aggregation and degeneration. We have a special interest in the roles that molecular chaperones play in neurodegenerative disorders. The long-term goals of our studies are to further develop our understanding of the cellular pathways and pathogenic mechanisms of neurodegenerative disorders, and to use information gained from mechanism based approaches to identify novel therapeutic targets for small molecules that could prevent neurodegeneration in humans.

Recently, we have made major progress in three areas. We have found that molecular chaperones may prevent toxicity of protein aggregates by reducing levels of potentially toxic aggregation intermediates. Using genome-wide screening approaches in yeast, we have discovered novel sets of genes that are crucial for the toxicity of protein aggregates associated with Huntington's and Parkinson's diseases. Finally, we have developed novel mouse models for analysis of the assembly and toxicity of protein aggregates in vivo. With these new experimental tools and approaches, we are in a unique position to make rapid advances in understanding the molecular basis of diseases associated with protein misfolding and aggregation.

Selected Publications

Giorgini, F., Guidetti P., Nguyen, Q.V., Bennett , S.C. & Muchowski, P.J., "A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease", Nat Genet. , 37(5), 2005.

Muchowski, P.J. and Wacker, J.L., "Modulation of neurodegeneration by molecular chaperones", Nat Rev Neurosci. , 6(1):11-22, 2005.

Wacker, J.L., Zareie, M.H., Fong, H., Sarikaya, M. and Muchowski, P.J., "Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer", Nat. Struct. and Mol. Biol. , 11(11):1215-1222, 2004.

Fleming, T.O. and Muchowski, P.J., "Molecular genetic approaches in yeast to study amyloid diseases", J. Mol. Neurosci. , 23:49 -60, 2004.

Willingham, S., Outeiro, T.F., DeVit, M.J., Lindquist, S.L. and Muchowski, P.J., "Yeast Genes that Enhance the Toxicity of a Mutant Huntingtin Fragment or a -synuclein", Science , 302(5651):1769-72, 2003.

Muchowski, P.J., "Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones?", Neuron , 35:9-12, 2002.

Muchowski, P.J., Ning, K., D'Souza-Schorey, C. and Fields, S., "Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment", Proc. Natl. Acad. Sci. U.S.A. , 99:727-732, 2002.

Muchowski, P.J., Shaffar, G., Sittler, A., Wanker, E.E., Hayer-Hartl, M.K. and Hartl, F.U., "Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils", Proc. Natl. Acad. Sci. U.S.A. , 97:7841-7846, 2000.

information last updated September 2005