Spinal Muscular Atrophy (SIVIA) is a devastating inherited neurodegenerative disease causing progressive loss of motor functions due to malfunction of neuromuscular junctions (NMJs) and eventual loss of motor neurons. SMA is caused by loss of Survival of Motor Neuron (SMN1), a component of the nuclear gemin complex which is thought to mediate assembly and transport of snRNP complexes and thus control the synthesis and delivery of key synaptic proteins. However, the identity and function of relevant SMN target genes and the precise molecular role of SMN at the NMJ remain largely a mystery. The proposed project focus will be to use simple genetic model systems to dissect the mechanism(s) by which SMN controls synaptic form and function, and thus identify likely targets for interventions to attenuate SMA in mammalian models or human patients. We will be using genetic approaches in Drosophila to identify functional modifiers of SMN mutations and will study them in both Drosophila as well as C.elegans (Artavanis-Tsakonas, van Vactor and Hart Laboratories). Mammalian cell assays (Rubin laboratory) will extend and corroborate the studies in invertebrates while possible functional relationships and pharmacological interventions identified in mammalian cells will be tested using the sophisticated genetic tools that C elegans and Drosophila offer. Each system has unique experimental advantages and the integration of the proposed analysis across vertebrates and invertebrates offers exceptional promise for an in depth understanding of SMN biology and pathology while, importantly, it carries the promise of identifying novel therapeutic avenues.

Public Health Relevance

Spinal Muscular Atrophy (SMA) is an often fatal childhood motor neuron disease. We propose to test molecules and pathways, identified in various types of screening campaigns, to see if they are able to prevent the degenerative changes that accompany this disease. Results of these studies could lead to novel therapeutics that reduce or eliminate the symptoms of SMA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Porter, John D
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Harvard University
Anatomy/Cell Biology
Schools of Medicine
United States
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Amaral, Andreia J; Brito, Francisco F; Chobanyan, Tamar et al. (2014) Quality assessment and control of tissue specific RNA-seq libraries of Drosophila transgenic RNAi models. Front Genet 5:43
Kwon, Deborah Y; Dimitriadi, Maria; Terzic, Barbara et al. (2013) The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein. Mol Biol Cell 24:1863-71
Berke, Brett; Wittnam, Jessica; McNeill, Elizabeth et al. (2013) Retrograde BMP signaling at the synapse: a permissive signal for synapse maturation and activity-dependent plasticity. J Neurosci 33:17937-50
Yang, Yin M; Gupta, Shailesh K; Kim, Kevin J et al. (2013) A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell 12:713-26
Dimitriadi, Maria; Kye, Min Jeong; Kalloo, Geetika et al. (2013) The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models. J Neurosci 33:6557-62
Ding, Qiurong; Lee, Youn-Kyoung; Schaefer, Esperance A K et al. (2013) A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12:238-51
Makhortova, Nina R; Hayhurst, Monica; Cerqueira, Antonio et al. (2011) A screen for regulators of survival of motor neuron protein levels. Nat Chem Biol 7:544-52