M.D., Holly Smith Distinguished Professor in Medicine & Chief, Medical Genetics UCSF
Dr. Nussbaum has his research efforts in three main areas. The first is an investigation of the genetic contribution to Parkinson disease (PD). Beginning ten years ago, in collaboration with his colleague Dr. Mihael Polymeropoulos, his group identified the first mendelian-inherited form of PD, a mutation in the gene encoding alpha-synuclein. Since then, he has been working to identify other inherited forms of the disease through family studies. Although inherited forms of PD are rare, the opportunity to discover and understand the pathogenetic mechanisms in rare hereditary forms of the disease gives insight into the pathways and processes that may be involved in the more common, sporadic forms. Dr. Nussbaum is using the information gained from the hereditary forms of the disease to develop disease models in mice using transgenic technology. A second area of research in the Nussbaum lab is a longstanding effort to understand the rare X-linked disease known as the oculocerebrorenal syndrome of Lowe (OCRL), characterized by congenital cataracts, Fanconi syndrome of the renal proximal tubules, neurological dysfunction, and developmental delay. Current treatment is purely symptomatic and palliative. Dr. Nussbaum discovered the gene responsible for OCRL by positional cloning and demonstrated that the gene encodes a phosphatidylinositol (4,5) bisphosphate 5-phosphatase that was shown to be enriched in the trans-Golgi network and early endosomal compartments. The relationship between the enzyme deficiency and the pathophysiological abnormalities in OCRL remain obscure. Surprisingly, mice engineered to lack the OCRL gene have no signs of the disease. Dr. Nussbaum is investigating why mice are protected from a deficiency in this enzyme and how this information might be exploited to expand our understanding of this enigmatic disorder and develop new, specific therapies.