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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Ahfeldt, Tim; Litterman, Nadia K; Rubin, Lee L (2016) Studying human disease using human neurons. Brain Res :
Sorkaç, Altar; Alcantara, Ivan C; Hart, Anne C (2016) In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9-Mediated Homologous Recombination Reveals Dominant Loss of Function Defects. PLoS One 11:e0167963
Anderson, Edward N; Corkins, Mark E; Li, Jia-Cheng et al. (2016) C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins. Mech Ageing Dev 154:30-42
Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika et al. (2016) Decreased function of survival motor neuron protein impairs endocytic pathways. Proc Natl Acad Sci U S A 113:E4377-86
Rigamonti, Alessandra; Repetti, Giuliana G; Sun, Chicheng et al. (2016) Large-Scale Production of Mature Neurons from Human Pluripotent Stem Cells in a Three-Dimensional Suspension Culture System. Stem Cell Reports 6:993-1008
Ng, Shi-Yan; Soh, Boon Seng; Rodriguez-Muela, Natalia et al. (2015) Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy. Cell Stem Cell 17:569-84
Brennand, Kristen J; Marchetto, M Carol; Benvenisty, Nissim et al. (2015) Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5:933-45
Schlaeger, Thorsten M; Daheron, Laurence; Brickler, Thomas R et al. (2015) A comparison of non-integrating reprogramming methods. Nat Biotechnol 33:58-63
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
Sen, Anindya; Dimlich, Douglas N; Guruharsha, K G et al. (2013) Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy. Proc Natl Acad Sci U S A 110:E2371-80

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