Spinal muscular Atrophy (SMA) is an autosomal recessive disease that can cause infant mortality. SMA is caused by the loss, or mutation, of the Survival Motor Neuron 1 gene (SMN1) and retention of the SMN2 gene. Both genes are ubiquitously expressed, but the majority of the product from the SMN2 gene lacks exon 7. This results in the SMN2 gene producing insufficient SMN protein for the correct function of motor neurons. The severity of the phenotype is modulated by SMN protein levels, which is influenced by the copy number of the SMN2 gene.
The aim of this proposal is to determine what factors activate SMN expression, which tissue, muscle or nerve requires high levels of SMN and whether a genetic system capable of identifying the critical function of SMN for motor neurons can be developed. This will help address the question: Why does deficiency of SMN cause a motor neuron disorder? We will determine what is required for activation of SMN expression by identifying the transcription factors that bind the SMN promoter. We will determine what tissue requires high levels of SMN by making mice that express SMN in either muscle or motor neurons, and asking which of these mouse lines can correct the SMA phenotype. This experiment will also address whether motor neurons are uniquely sensitive to SMN levels. The SMN levels will not be restored in non-cholinergic neurons. If SMN's splicing function is impaired due to low levels of the protein, these cells should degenerate. To develop a genetic model system which can be used in suppressor screens, which are capable of identifying the critical function of SMN in motor neurons, we are developing a zebrafish model of SMA. The zebrafish SMA model will also allow precise studies on the motor neuron development in SMA. The grant will define the transcriptional targets, which could be used for treatment of SMA, the tissue that requires high levels of SMN and will give a genetic system to define the function lacking in SMA. These developments will be important in developing treatments for SMA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS041649-01
Application #
6335855
Study Section
Special Emphasis Panel (ZNS1-SRB-R (01))
Program Officer
Leblanc, Gabrielle G
Project Start
2001-06-01
Project End
2005-06-01
Budget Start
2001-06-01
Budget End
2002-06-01
Support Year
1
Fiscal Year
2001
Total Cost
$330,750
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Gavrilina, Tatiana O; McGovern, Vicki L; Workman, Eileen et al. (2008) Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet 17:1063-75
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Sharma, Aarti; Lambrechts, Anja; Hao, Le Thi et al. (2005) A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells. Exp Cell Res 309:185-97
Majumder, Sarmila; Varadharaj, Saradhadevi; Ghoshal, Kalpana et al. (2004) Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene. J Biol Chem 279:14803-11
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