We study fundamental cellular processes relevant to human disease. A major research 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 to identify 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 such as cystic fibrosis or Parkinson’s will require a detailed understanding of the cellular protein quality control machinery.