Faculty Research

Henry L. Paulson, M.D., Ph.D.
Lucile Groff Professor of Neurology

My laboratory studies the mechanisms of age-related neurodegenerative diseases with a view to developing therapies. My clinical interests, which tie in closely with my research focus, include neurodegenerative disease of aging, movement disorders and neurogenetics. As we only recently moved to the University of Michigan, our lab website is still under construction. Here is a brief overview of our laboratory interests:

One major research focus is the group of neurodegenerative disorders caused by polyglutamine expansions, including Huntington disease and at least six Spinocerebellar Ataxias or SCAs. Polyglutamine expansion causes the disease protein to misfold and aggregate in brain cells, resulting in cell death through still uncertain mechanisms. We use various experimental approaches to explore disease including recombinant protein studies, cellular models, transgenic mice and analysis of human disease tissue. Major goals of this research are to: 1) determine how neurons "handle" abnormal protein; 2) define the consequences of protein misfolding for the neuron; 3) identify the function of the polyglutamine disease protein, ataxin-3, which has unusual properties; and 4) design a better mouse model for future studies of pathogenesis and preclinical drug trials.

A second area of interest is turning off disease genes as a potential therapy for untreatable disorders. It is now clear that many neurodegenerative disease proteins are toxic to neurons. Accordingly, we use the power of RNA interference (RNAi) to "silence" neurodegenerative disease genes, including polyglutamine disease genes and Alzheimer disease genes. Employing animal models of disease, we hope to determine whether this potential therapeutic strategy holds promise in humans. A major goal in the next five years is to push this technology toward the clinic.

In other studies, we investigate the complex machinery that regulates protein "quality control" in the brain. In neurons, the ubiquitin-proteasome and chaperone pathways are important not only for eliminating toxic proteins but also for destroying normal proteins. Quality control is important for normal brain function. We have identified a novel family of ubiquitin ligases that regulate glycoprotein homeostasis (proteins with attached sugars). Molecular, cellular and animal knockout approaches are being used to define the role of these ubiquitin ligases in the brain and elsewhere. For example, we recently discovered that knockout of one such gene, Fbx2, leads to cochlear degeneration.

Selected, recent articles of relevance:

Rodriguez-Lebron E. Paulson H. Allele-specific RNA interference for neurological disease. Gene Therapy 13(6):576-81, 2006.

Nelson RF, et al. An alternative route for F-box protein mediated ubiquitination links CHIP to glycoprotein quality control. J. Biol. Chem. 281(29):20242-51, 2006.

Nelson RF, et al. Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit. J. Neuroscience 27:5163-71, 2007.

Gonzalez-Alegre P, Paulson H. Therapeutic RNA interference: how far from the neurology clinic? Nature Clinical Practice Neurology 3(7):394-404, 2007.

Nopoulos P, et al. Morphology of the cerebral cortex in preclinical Huntington's disease. Am J Psychiatry 164(9):1428-34, 2007.

Paulson, HL. Dominantly inherited Ataxias: Lessons learned from Machado-Joseph Disease/Spinocerebellar Ataxia type 3. Seminars in Neurology, 27(2):133-142, 2007.

Soong B-W, Paulson HL. Spinocerebellar ataxias: An update. Current Opinion in Neurology 20(4):438-446, 2007.

Todi SV, et al. Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity. J. Biol. Chem., Aug. 10, [Epub ahead of print], 2007.