Paul Muchowski, PhD
Associate Investigator
Gladstone Institute of Neurological Disease
Associate Professor of Neurology
University of California, San Francisco
Email: pmuchowski@gladstone.ucsf.edu
Telephone: 415-734-2515
Fax: 415-355-0824

Areas of Investigation
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 (AD), Huntington’s disease (HD) and Parkinson’s disease (PD). Our long-term goal is to use information gained from mechanism-based approaches to identify novel therapeutic targets for small molecules that could prevent neurodegeneration in humans.

Significance
A growing number of neurodegenerative disorders are caused by mutations that result in altered protein conformations, often leading to a gain of function for the mutant protein. For many of these diseases, structural alterations in the mutant proteins lead to the accumulation of insoluble, ubiquitinated protein aggregates that are found inside and sometimes outside of the affected cells. In many cases the aggregates adopt an ordered fibrillar structure rich in β-sheet called amyloid, which has been implicated in the pathology of numerous human diseases. The cellular pathways and molecular mechanisms by which abnormal protein conformations give rise to neuronal dysfunction and cell death remain poorly understood and are being actively investigated in our laboratory.

Approaches
We utilize a broad array of research tools and methods in our studies, including structural analyses of protein aggregation reactions, genetic screens in simple yeast models to identify proteins that modulate aggregation and toxicity of disease-causing proteins, and molecular-genetic/chemical-genetic approaches in cellular and animal models of AD, HD and PD. We have a special interest in understanding the role that molecular chaperones play in these disorders.

Contributions We have recently made major progress in three areas. We have found that molecular chaperones may prevent toxicity of abnormal protein conformations 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 proteins linked to HD and PD. 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 abnormal protein conformations and aggregation.

Questions Addressed in Ongoing Studies

• What is the structural nature of abnormal protein conformations that trigger neurodegeneration?
• How do abnormal protein conformations mediate aberrant protein interactions that trigger neurodegeneration?
• How do chaperones mediate protection against neurodegeneration?
• Can we use genetic approaches to identify the cellular pathways and networks that mediate neurodegeneration?
• What role do glia play in neurodegeneration?
• Can we identify genes encoding druggable protein targets that modify toxicity of disease-causing misfolded proteins?
• Can we identify small molecules that block cellular pathways important for neurodegeneration?

Selected Publications

 
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