I am currently a joint postdoctoral fellow working in the laboratories of Dr. Mustafa Sahin and Dr. Judith Steen. My research involves characterizing proteins and mRNA targets that interact with the SMN protein in the nervous system.
Spinal Muscular Atrophy (SMA), a disease caused by the deletion of survival motor neuron 1 (SMN) gene, is the most common genetic cause of infant mortality. Humans have two copies of the SMN gene, the telemoric SMN1 which encodes for a full-length form, and the centromeric SMN2 which encodes primarily for a truncated form. The SMN2 gene lies in a region of chromosome 5q where there are multiple gene rearrangements and duplications, and individuals with more copies of the SMN2 gene manifest a less severe form of SMA (Type III SMA). In the most severe form, Type 1 SMA, there are 1-2 copies of the SMN2 gene, and patients die within 2 years of age due to respiratory failure. SMN protein is expressed ubiquitously in all cell types and is found both in the cytoplasm and nucleus. It is involved in a variety of cellular processes including small nuclear ribonucleoproteins (snRNP) biogenesis, pre-mRNA splicing, transcriptional/translational activation, and axonal transport. Although SMN is expressed in several tissues and functions in diverse cellular processes, it is unclear as to why only the anterior horn motor neurons of the spinal cord are affected. In addition, the heterotopic (migratory) motor neurons have been a hallmark in the pathogenesis of SMA, indicating that SMN is critical for survival of motor neurons during development and differentiation.
To explore the migrational defects further, we investigated mRNAs that may be targeted by SMN within the axons. One such mRNA coimmunoprecipitates with SMN from mouse spinal cords and its levels decrease when SMN levels are reduced by shRNAs in hippocampal cell cultures. Experiments are being conducted in vitro to understand the biology of this interaction, and in vivo to confirm its importance in the pathogenesis of SMA.