Mentors: Rob Mason, PhD and Carolyn Schanen, MD, PhD
Investagator: Dr. Wenlan Wang, MD, PhD (Matthew Butchbach, PhD)
Systematic Analyses of SMN Complexes in Motor Neurons
Spinal muscular atrophy (SMA) is an autosomal genetic disease caused by deletion or mutation(s) of the survival motor neuron gene 1 (SMN1). The hallmark of SMA is death of spinal motor neurons and muscle paralysis. SMA occurs in 1:6000 live births, and thus is one of the most common genetic causes of infant death.
The long-term goal of our research is to understand the mechanism(s) of spinal motor neuron death in SMA and to develop a means to prevent neuronal cell death. Our preliminary studies show that skin fibroblasts from SMA patients display increased sensitivity to some death-promoting stimuli [1], and primary motor neuron cultures are much more sensitive to this death-promoting stimuli when compared with normal fibroblasts.This has led us to hypothesize that SMN plays a role in cell survival; increased vulnerability of motor neurons to the loss of SMN’s survival function leads to motor neuron death in SMA.
The objective of this proposal is to systematically analyze compositionof SMN complexes in motor neurons that are likely responsible for motor neuron survival. This could lead to answer a critical question for understanding SMA pathogenesis, which is why reduced levels of the ubiquitously expressed SMN protein selectively affect motor neurons. Here, we will leverage our expertise in cell death mechanism and motor neuron biology and cutting edge proteomics at Delaware Biotechnology Institute proteomics core directed by Dr. Kelvin Lee to dissect the SMN complexes in motor neurons.
We will achieve this in the following aims: 1). We will determine the composition of SMN complexes in motor neurons. 2). We will determine distribution of SMN complexes in subcellular compartments in motor neurons. 3). We will also determine if reduced levels of SMN cause defective SMN complex formation in motor neurons. The results from the proposed studies will provide insight into the mechanism(s) by which SMN function specifically in motor neurons and how SMN-deficiency leads to SMA phenotype. Ultimately, the information obtained could lead to development of therapeutic strategies to intervene.
Staff and Student Participants:
Dosh Whye - Research Assistant
Chia-Yen Wu - Graduate Student