Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive motor neuron disease that is the leading inherited cause of infant mortality. SMA is caused by deficiency of the survival motor neuron (SMN) protein. Our long term research goal is to understand the underlying pathogenesis of SMA in order to develop effective treatment strategies for this disease. Recent studies suggest that SMA begins because of intrinsic abnormalities of both muscle and motor nerve terminals;however the nature of these defects remains unknown. Histone deacetylase (HDAC) inhibitors have been shown to increase survival of SMA mice;but it is unclear how these drugs improve muscle and/or motor neuron function. In preliminary studies in SMA mice, we have shown that at a time when the mouse is profoundly weak, there is little structural denervation. However there are widespread immature and hypotrophic myofibers as well as simplified neuromuscular junctions (NMJs). Mice treated with a pan- HDAC inhibitor show a substantial extension of survival, increase in motor function, and improvement in the size and maturity of myofibers, without a change in motor neuron number. Based on these preliminary data, we hypothesize that SMN deficiency causes an arrest of muscle maturation and/or a failure of NMJ transmission that can be overcome with HDAC inhibitors, which accelerate the development of the SMA motor unit. We further hypothesize that HDAC isoform-specific drugs will have distinct biological effects on the SMA motor unit that will provide crucial insights into the therapeutic mechanism of these compounds. We will test these hypotheses by: 1) establishing whether or not a defect of muscle development contributes to SMA by studying cultured SMA muscle cells and by rescuing SMN expression specifically in muscle tissue in conditional SMA mice, 2) determining whether or not weakness in SMA is due to an impairment of neuromuscular transmission by examining the electrophysiology and morphology of the NMJs in SMA mice, and 3) characterizing the ability of HDAC inhibitors to facilitate muscle and NMJ maturation and ameliorate SMA in mice by treating SMA muscle cells and SMA mice with broadly active and HDAC-isoform specific HDAC inhibitors.

Public Health Relevance

This work is important for public health because spinal muscular atrophy is the leading inherited cause of infant mortality and is currently untreatable. In this project, we plan to define the roles of muscle and motor neuron terminals in the pathogenesis of SMA and to explore the therapeutic mechanism of histone deacetylase inhibitors. These studies will provide important insights about what tissue and molecules are necessary to target therapeutically in SMA and will therefore guide future efforts to develop treatment for this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CDIN-T (03))
Program Officer
Porter, John D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Rindt, Hansjörg; Feng, Zhihua; Mazzasette, Chiara et al. (2015) Astrocytes influence the severity of spinal muscular atrophy. Hum Mol Genet 24:4094-102
d'Ydewalle, Constantin; Sumner, Charlotte J (2015) Spinal Muscular Atrophy Therapeutics: Where do we Stand? Neurotherapeutics 12:303-16
Miller, Nimrod; Feng, Zhihua; Edens, Brittany M et al. (2015) Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy. J Neurosci 35:6038-50
Bricceno, Katherine V; Martinez, Tara; Leikina, Evgenia et al. (2014) Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Genet 23:4745-57
Sumner, Charlotte J; d'Ydewalle, Constantin; Wooley, Joe et al. (2013) A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance. Am J Hum Genet 93:976-83
Van Meerbeke, James P; Gibbs, Rebecca M; Plasterer, Heather L et al. (2013) The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum Mol Genet 22:4074-83
Tisdale, Sarah; Lotti, Francesco; Saieva, Luciano et al. (2013) SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3'-end formation of histone mRNAs. Cell Rep 5:1187-95
Paez-Colasante, Ximena; Seaberg, Bonnie; Martinez, Tara L et al. (2013) Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons. PLoS One 8:e75866
Martinez, Tara L; Kong, Lingling; Wang, Xueyong et al. (2012) Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci 32:8703-15
Bricceno, Katherine V; Sampognaro, Paul J; Van Meerbeke, James P et al. (2012) Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice. Hum Mol Genet 21:4448-59

Showing the most recent 10 out of 19 publications