Henry L Paulson M.D., Ph.D.
| Ann Arbor, MI 48109 |
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My lab, which moves to the University of Michigan in the summer of 2007, explores the reasons why the brain degenerates in various neurodegenerative diseases. While we have focused particularly on the polyglutamine expansion diseases, we also study genes implicated in Alzheimer disease. A common theme among neurodegenerative diseases is the tendency for certain proteins to misfold and aggregate in select brain regions. We investigate why these proteins are toxic to neurons and how the neuron's protein quality control machinery (e.g., molecular chaperones, ubiquitin-proteasome degradation system) counteracts this toxicity. To address these questions, we employ techniques ranging from recombinant protein analysis to cell-based assays and engineered mouse models, with corroborating analysis of human disease tissue when needed. Our long-term goal is to understand disease processes so that we can develop therapies for these fatal, curently untreatable disorders. Toward that end, we were among the first to use RNA interference as a potentially powerful therapeutic strategy for such disorders. In the next few years, we will continue preclinical studies of therapeutic RNAi as we and others strive to bring this novel approach to treatment to the clinic.
Gonzalez-Alegre P, and Paulson H. (2007) Therapeutic RNA interference: how far from the neurology clinic? Nature Clinical Practice Neurology (in press)
Nelson R.F., et al. (2007) Selective Cochlear Degeneration in Mice Lacking the F-box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit. J. Neuroscience 27, 5163-71
Todi S., and Paulson H. (2007) Dangerous Liaisons: PolyQ meets HMGB. Nat Cell Biol. 9, 359-61.
Nelson R.F., et al. (2006) An alternative route for F-box protein mediated ubiquitination links CHIP to glycoprotein quality control. J Biol Chem 281 (29), 20242-51
Gonzalez-Alegre P., et al.(2005) Silencing primary dystonia: lentiviral-mediated RNA interference therapy for DYT1 dystonia. J Neuroscience 25 (45), 10502-9
Miller V.M., et al.. (2005) CHIP Suppresses Polyglutamine Aggregation and Toxicity In Vitro and In Vivo. J Neuroscience 25 (40), 9152-61
Berke S.J.S., et al. (2005) Defining the role of ubiquitin interacting motifs in the polyglutamine disease protein, ataxin-3. J Biol Chem 280 (36), 32026-34
Harper, S.Q., et al. (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Nat. Acad. Sci. U.S.A. 102 (16), 5820-5825
Paulson, H.L., and V.M. Miller. (2005) Breaks in coordination: DNA repair in inherited ataxia. Neuron 46, 845-848
Warrick, J., et al. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol. Cell 18, 37-48
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