Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is the most common genetic cause of death in infancy, but no effective treatment is currently available. Reduced levels of the survival motor neuron (SMN) protein cause SMA. Although the SMN complex is a multifunctional machine involved in several aspects of RNA metabolism, its best molecularly defined function is in the assembly of the small nuclear ribonucleoproteins (snRNPs) that are essential for post-transcriptional RNA regulation, including pre-mRNA splicing and 3'-end processing of histone mRNAs. Recently, we demonstrated that SMN-dependent splicing events are essential for motor neuron function in vivo and directly linked defective splicing of a gene with essential neuronal functions to the phenotypic consequences of SMN deficiency in animal models of SMA. These findings revealed disruption of SMN function in snRNP assembly as the molecular mechanism underlying SMA pathology. The identification of signaling pathways that regulate SMN function is critical not only for revealing fundamental aspects of post- transcriptional gene regulation but also strategies for SMA therapy. However, little is known of post- translational modifications that control SMN biology. In preliminary studies, we have found that SMN is modified by SUMO (Small Ubiquitin-like Modifier) and that inhibition of sumoylation alters SMN subcellular distribution. Sumoylation is a reversible post-translational modification involved in a variety of cellular processes. Importantly, sumoylation has been implicated in the pathogenesis of amyotrophic lateral sclerosis, Huntington's and Alzheimer's diseases. This project will investigate our hypothesis that sumoylation of the SMN complex is a regulatory mechanism for the control of snRNP biogenesis and other RNA processes that are disrupted in SMA.
In Specific Aim 1, we will use cell model systems to determine the requirement of sumoylation for the expression, stability, localization and function of the SMN complex.
In Specific Aim 2, we will investigate the link between sumoylation of SMN and SMA pathology. To achieve this, we will study the function of wild-type and non-sumoylatable SMN mutants using AAV-mediated expression in a mouse model of SMA to determine whether SMN sumoylation is required for the critical in vivo function whose disruption contributes to SMA pathology. Successful completion of this project will reveal the role of sumoylation in the regulation of SMN biology. In addition to the relevance for unraveling novel regulatory networks that control fundamental RNA-dependent cellular processes, this project has the potential to link sumoylation to SMA pathology and open the way for future studies of this pathway as a candidate therapeutic target for this devastating human disease.

Public Health Relevance

Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and the leading hereditary cause of infant mortality. SMA is caused by reduced levels of the survival motor neuron (SMN) protein. This project will investigate the role of SMN's post-translational modifications in the control of the fundamental cellular processes contributing to SMA etiology. By linking SMN's post-translational modifications to SMA pathology this project could open the way to novel therapeutic strategies for SMA and possibly other related neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Nuckolls, Glen H
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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