Through an intimate set of collaborative interactions with three other laboratories working in invertebrate and mammalian systems, we have developed a genome-wide approach to define the conserved funcfional """"""""interactome"""""""" for Survival of Motor Neurons (SMN), the highly conserved genefamily causal to over 95% of Spinal Muscular Atrophy (SMA), one of the most common degenerative motor neuron diseases in humans. Through recent studies, Drosophila has emerged as a promising genefic model for Smn with the key hallmarks of human SMA, from failure of neuromuscular junctions to the degeneration of neurons and muscles. Despite an emphasis in the SMA field to focus on mouse models, the innovative use of invertebrate species to understand SMN biology and define conserved and potentially druggable effector pathways was recently supported by a patient advocacy group (the SMA Foundation). Our analysis of Smn modifier mutations and compounds/factors derived from chemical and genetic screens in Drosophila, C. elegans and human cells has identified several strong and conserved candidate pathways, including the Bone-Morphogenic Protein (BMP)-family signaling pathway known to control neuromuscular juncfion (NMJ) development in flies. Modulafion of this BMP retrograde synaptic signaling pathway alone can potently attenuate key NMJ phenotypes of Smn loss in Drosophila. Therefore, in addition to completion of our secondary screens to define the Smn functional network, we here propose parallel levels of analysis to determine precisely how loss of Smn disrupts BMP signaling, and to what extent manipulation of the highly conserved elements in the BMP pathway can reverse the defects in neuromuscular structure and function resulting from reduced Smn acfivity. We will apply a combinafion of genefic, biochemical and developmental analyses to answer these questions, as we continue to identify the other conserved effectors downstream of SMN.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
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

Showing the most recent 10 out of 23 publications