Using Drosophila as our experimental system, we propose employing molecular genetic approaches to identify and characterize genetic modifiers of SMN, as such modifiers may define potential therapeutic targets for Spinal Muscular Atrophy (SMA). The available experimental reagents will allow us to probe tissue-specific (muscle vs. neuron) roles for SMN and its known modifiers at the Drosophila neuromuscular junction (NMJ), and to perform a high-throughput genetic screen to identify modulators of SMN activity using a novel SMN mutation and a unique collection of Drosophila mutations. In view of processes thought to be linked to SMN activity in the muscles and neurons, we propose to characterize functional modifiers of SMN specifically associated with the cytoskeleton and protein translation (Aim 1). In addition, we will further examine our initial observation that FGF signaling activity modifies NMJ abnormalities caused by loss of SMN function. This role will be evaluated in the context of a novel, SMN dependent, muscle deterioration phenotype we uncovered (Aim 2). Finally, we will extend our genetic screens for SMN modifiers using hypomorphic SMN alleles, which provide an improved SMA model and will also use behavioural assays to evaluate the activity of specific adult motorneurons (Aim 3). Our studies will be evaluated in light of a hitherto unprecedented characterization of the Drosophila NMJ (Van Vactor laboratory) while our other collaborative efforts, will permit us to validate results across species in C. elegans (Hart laboratory) and mammalian cells (Rubin laboratory).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS066888-04
Application #
8509035
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$295,835
Indirect Cost
$121,303
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Rodriguez-Muela, Natalia; Parkhitko, Andrey; Grass, Tobias et al. (2018) Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest 128:3008-3023
Rodriguez-Muela, Natalia; Litterman, Nadia K; Norabuena, Erika M et al. (2017) Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease. Cell Rep 18:1484-1498
O'Hern, Patrick J; do Carmo G Gonçalves, Inês; Brecht, Johanna et al. (2017) Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models. Elife 6:
Riessland, Markus; Kaczmarek, Anna; Schneider, Svenja et al. (2017) Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis. Am J Hum Genet 100:297-315
Ahfeldt, Tim; Litterman, Nadia K; Rubin, Lee L (2017) Studying human disease using human neurons. Brain Res 1656:40-48
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
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
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
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 5:933-945

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