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The Role of Muscle and Nerve in Spinal Muscular Atrophy

Iyer, Chitra C

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2016, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant death, affecting approximately 1 in 10,000 live births worldwide. SMA is caused due to decrease in levels of the ubiquitous Survival Motor Neuron (SMN) protein. SMN in humans is encoded by two genes SMN1 and SMN2. SMA is an autosomal recessive disease caused due to deletion or mutation of SMN1 and retention of SMN2. Due to a C to T change in SMN2, the gene produces only small amounts of full-length SMN protein. In SMA patients, the low levels of SMN lead to degeneration of motor neurons and muscle atrophy. Since SMA is characterized by muscle atrophy, blocking of muscle ubiquitin ligases that degrade sarcomeric proteins is a prospective therapy. We deleted two muscle-specific ubiquitin ligases, MAFbx and MuRF1, in severe SMA mice. Deletion of MAFbx did not improve the phenotype or survival of SMA mice, and MuRF1 deletion in the SMA mice turned out to be deleterious. MAFbx and MuRF1 levels are upregulated in the skeletal and cardiac muscle in SMA. We conclude that deletion of muscle ubiquitin ligases in SMA does not improve the phenotype of SMA mice. With various clinical trials in action in the field of SMA, understanding the spatial requirement of SMN protein is crucial. SMN is a ubiquitous protein but a decrease of SMN in SMA causes degeneration of motor neurons and muscle atrophy. To study the relative importance of either tissue, we employed tissue specific Cre drivers and floxed mouse Smn alleles. We selectively decreased SMN in the neurons or the muscle and conversely restored SMN levels in the neurons or the muscle. Our studies show that 2 copies of SMN2 (and SMN¿7) produce sufficient SMN for the normal function of muscle. Decreasing SMN to SMA levels in skeletal muscle, using Myf5-Cre driver, does not affect the mice. Importantly, the force production capacity of the muscle is unaltered. The muscle fiber size distribution and electrocardiogram of mice with low SMN in muscle is comparable to normal. Replacement of SMN levels in solely the muscle does not improve the SMA phenotype. In the neuron set of experiments, we found that decreasing or restoring SMN in only the motor neurons with ChAT-Cre significantly alters the functional output of the motor unit as measured by compound motor action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice upon Smn-replacement and did not appreciably affect survival when used to delete Smn. On the other hand, replacement of Smn in both neurons and glia in addition to the motor neurons (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons has a major impact on survival.
Arthur Burghes, Dr. (Advisor)
Daniel Battle, Dr. (Committee Member)
Brian Kaspar, Dr. (Committee Member)
Jiyan Ma, Dr. (Committee Member)
216 p.

Recommended Citations

Citations

  • Iyer, C. C. (2016). The Role of Muscle and Nerve in Spinal Muscular Atrophy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1451568269

    APA Style (7th edition)

  • Iyer, Chitra. The Role of Muscle and Nerve in Spinal Muscular Atrophy. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1451568269.

    MLA Style (8th edition)

  • Iyer, Chitra. "The Role of Muscle and Nerve in Spinal Muscular Atrophy." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1451568269

    Chicago Manual of Style (17th edition)