As human longevity increases, understanding the mechanisms that drive aging becomes ever more critical. We study the premature aging disorder Hutchinson Gilford Progeria Syndrome to gain molecular insights into aging, focusing on the nuclear scaffold protein lamin A and its proteolytic processing enzyme ZMPSTE24, since mutations in either can cause progeria.
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Susan Michaelis, Ph.D.
Susan Michaelis, Ph.D.website
Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe Street, 106 Biophysics
Baltimore, MD 21205
Research Topic : Progeria and lamin A processing by the ZMPSTE24 protease; ERAD and cytosolic protein quality control; yeast and mammalian cell biology.
The overall goal of our research is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry, and high-throughput genomic approaches. A current focus in our laboratory is the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS), which results from a mutation in the gene encoding the nuclear scaffold protein lamin A. Children with HGPS exhibit profound characteristics of aging, including hair loss, skin and bone defects, and heart disease. The mutant form of lamin A in HGPS patient cells is persistently modified by the lipid farnesyl, an aberrant situation, since normally cleavage by the ZMPSTE24 protease removes the farnesylated C-terminal tail of lamin A during biogenesis. We are examining the cell biology of lamin A processing, the molecular mechanisms of lamin A toxicity in HGPS, mechanistic features of the ZMPSTE24 membrane protease, therapeutic strategies, and the link between HGPS and normal aging.
We also study protein quality control mediated by the ubiquitin-proteasome system. Misfolded secretory and membrane proteins are efficiently degraded by ER-associated degradation (ERAD), while cytosolic quality control (CytoQC) pathways handle misfolded soluble proteins. Our goal is toidentify the core cellular machinery involved in recognition of misfolded proteins, using model proteins as 'bait' in genome-wide yeast screens designed to uncover the eukaryotic ERAD and CytoQC machinery. Ultimately devising treatment for protein misfolding diseases in which degradation is too efficient (e.g. cystic fibrosis) or not efficient enough (e.g. neurological disorders like Parkinson’s)will rely on a detailed understanding of cellular protein quality control machinery.
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