Spinal Muscular Atrophy (SMA), a disease caused by the mutations of Survival Motor Neuron 1 (SMN1) gene, is the most common genetic cause of infant mortality. Humans have two copies of the SMN gene, the telomeric SMN1, which encodes for a full-length form (FL-SMN), and the centromeric SMN2, which encodes primarily for a rapidly-degraded truncated form (SMN 7) as well as the full-length form. In the most severe form, Type 1 SMA, there are 1 or 2 copies of the SMN2 gene, and patients die within 2 years of age due to respiratory failure. Patients with more copies of the SMN2 gene, however, manifest a less severe form of SMA (Type III SMA). SMA occurs due to decreased amount of FL-SMN protein in spinal motor neurons. Therefore, much of the effort for therapeutic interventions in SMA has focused on increasing the level of FL-SMN protein products. Our preliminary results show that SMN is found in a complex containing an E3 ubiquitin ligase the Anaphase- Promoting Complex (APC) and HuD, a RNA binding protein. The APC targets proteins to the proteasome for degradation whereas HuD stabilizes mRNAs. Furthermore, evidence indicates a role for APC in neuronal survival, axonal growth, and synaptic function, and HuD is involved in the maturation and maintenance of neurons. We also know from previous studies that SMN may be necessary for the transport, stability and/or translation of certain mRNAs in neurites. These data together prompted us to formulate a working model in which: 1) ubiquitination by APC regulates the stability and/or function of SMN or other members of the SMN complex and 2) the putative HuD-SMN-associated mRNAs in axons are important for the growth and survival of motor neurons. In the first part of this application, we will investigate the role of APC in regulation of SMN stability and function. We will first characterize the interaction between APC and SMN in neurons. Then, we will investigate the effect of inhibiting the APC-SMN interaction on the function, stability, localization, of SMN protein. In the second part, we will focus on one axonal SMN target mRNA which is likely to play a role in axon outgrowth. Since there is a tight correlation between the amount of FL-SMN and the severity of disease, understanding the interaction between APC and SMN as well as elucidating the downstream targets of SMN will provide important insights into the biology of SMA and has the potential to generate new treatment options for this disease.

Public Health Relevance

Spinal muscular atrophy (SMA) is the leading genetic cause of infant deaths in the United States. We propose to investigate the cellular mechanisms of this disease using state of the art proteomics and RNA analysis. Understanding these cellular mechanisms may ultimately be important for designing therapies for SMA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Porter, John D
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Children's Hospital Boston
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