Division of Genetics and Developmental Medicine

My research is focused in two areas. The first is a juvenile-onset form of motor neuron disease (amyotrophic lateral sclerosis type 4) which results from mutations of the Senataxin (SETX) gene. We have generated mammalian expression constructs of wild type SETX and three mutant forms of SETX associated with ALS4. We found the amount and molecular weight of the SETX protein isolated from ALS4 patient lymphoblasts is approximately equal to that from controls. We have completed preliminary studies of the wild type SETX protein and determined that SETX is a ~ 400-kDA, cytoplasmic and nuclear protein. SETX protein is expressed in most tissues but is cell-type specific. For example in the brain, SETX expression is prominent in neuronal populations. Most importantly, we have produced murine ALS4 transgenic founders that will likely prove extremely important to understand the mechanism leading to motor neuron death resulting from SETX mutations. Additionally, as we already have a vested interest in studying the Senataxin protein (gain-of-function mutations associated with ASL4), it will be particularly important to obtain preliminary data from Ataxia-ocular apraxia (AOA2) patients which represent recessive loss-of-function mutations of SETX.

The second area is Charcot-Marie-Tooth neuropathy type 1C (CMT1C). We have already shown that the SIMPLE protein (which, through mutation, causes CMT1C), interacts with two proteins, NEDD4 and TSG101 that act sequentially in the lysosomal sorting pathway. Our results show that SIMPLE co-localizes with NEDD4 at the plasma membrane and the Golgi apparatus. Finally, we examined mutant forms of SIMPLE associated with CMT1C and found that these mutations do not affect interaction with either NEDD4 or TSG101; nor do they affect normal subcellular localization of SIMPLE protein in several cultured cell lines. The next stage of our research will focus on the precise function of SIMPLE in primary Schwann cell cultures.