Regulation of SMN Stability and Identification of its Downstream Targets

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by loss of the motor neurons in the spinal cord and the brain stem nuclei. The SMN1 (survival motor neuron) gene is the primary SMA disease-causing gene. The SMN protein is ubiquitously expressed and interacts with a number of essential components of RNA biogenesis and splicing. In humans, there is a second gene (SMN2) whose copy number is highly variable. SMN2 is a modifier of disease severity such that individuals with SMN1 mutation and high copy number of SMN2 have a milder form of the disease. Therefore, levels of SMN protein appear to be critical to the severity of the illness. As a result, much of the effort for therapeutic interventions has focused on increasing the stability of SMN protein products. An alternative approach is to determine the mRNA targets of SMN and use the protein product of these mRNAs to reduce the severity of the disease. Thus, examining transcripts regulated by SMN may be critical to understanding the pathology of SMN. In this project, we are using a combination of biochemistry and proteomic techniques to investigate both cellular mechanisms: 1) stabilizing SMN protein and 2) characterizing the regulation of a gene product that is affected by SMN expression. A combination of these two approaches will enable us to delve more deeply into the regulation of SMN degradation and SMN regulation of mRNAs in neurites. Understanding these cellular mechanisms may ultimately be important for designing therapies for SMA.