Andrew Lieberman, M.D., Ph.D.

The Lieberman Lab studies inherited neurodegenerative diseases to understand neurological dysfunction mechanisms 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 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 how 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 with 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 leads to glycosphingolipids' predominant accumulation within neurons. Mutations cause most cases of Niemann-Pick C in Npc1, a gene widely expressed in the brain. It is not 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 study the mechanisms leading to neuron death.