Our laboratory studies inherited neurodegenerative diseases, with the goal of understanding the mechanisms underlying neurological dysfunction so as to develop effective treatments. We are particularly interested in the CAG repeat diseases, a group of nine genetically related disorders caused by expanded CAG/glutamine tracts in the coding regions of disease-causing genes. Among these disorders is Kennedy disease, a degenerative disease that predominantly affects lower motor neurons and is caused by a mutation in the androgen receptor gene. The mutant protein misfolds, aggregates, and abnormally interacts with other proteins, leading to both a toxic gain-of-function and a partial loss of normal function. We have developed both a knock-in mouse model and cell culture models of Kennedy disease. We are using these systems to understand the mechanisms by which the mutant androgen receptor causes selective neuronal dysfunction that is characteristic of this disorder and to test novel therapeutic approaches.
Our laboratory also studies Niemann-Pick C, an autosomal recessive neurovisceral lipid storage disease for which there is no cure. Mutations in two genes, Npc1 and Npc2, produce a clinically heterogeneous disorder characterized by devastating neurodegeneration that often begins in childhood. Loss of function mutations in either gene disrupts lipid trafficking and lead to the predominant accumulation of glycosphingolipids within neurons. Most cases of Niemann-Pick C are caused by mutations in Npc1, a gene widely expressed in the brain. It is not currently known which cells are mechanistically involved in the neuropathology characteristic of this disease or whether the proteostasis machinery can be manipulated to achieve a functional rescue. We are using cellular and mouse models of Niemann-Pick C to address these questions and to study the mechanisms that lead to neuron death.