RRC ID 59423
Author Wu CY, Gagnon DA, Sardin JS, Barot U, Telenson A, Arratia PE, Kalb RG.
Title Enhancing GABAergic Transmission Improves Locomotion in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.
Journal eNeuro
Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of spinal motor neurons resulting in variable degrees of muscular wasting and weakness. It is caused by a loss-of-function mutation in the survival motor neuron (SMN1) gene. Caenorhabditis elegans mutants lacking SMN recapitulate several aspects of the disease including impaired movement and shorted life span. We examined whether genes previously implicated in life span extension conferred benefits to C. elegans lacking SMN. We find that reducing daf-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this C. elegans model of SMA. The locomotor dysfunction in C. elegans lacking SMN correlated with structural and functional abnormalities in GABAergic neuromuscular junctions (NMJs). Moreover, we demonstrated that reduction in daf-2 signaling reversed these abnormalities. Remarkably, enhancing GABAergic neurotransmission alone was able to correct the locomotor dysfunction. Our work indicated that an imbalance of excitatory/inhibitory activity within motor circuits and underlies motor system dysfunction in this SMA model. Interventions aimed at restoring the balance of excitatory/inhibitory activity in motor circuits could be of benefit to individuals with SMA.
Volume 5(6)
Published 2018-1-1
DOI 10.1523/ENEURO.0289-18.2018
PII eN-NWR-0289-18
PMID 30627660
PMC PMC6325564
MeSH Adjuvants, Immunologic / pharmacology Animals Animals, Genetically Modified Biomechanical Phenomena / drug effects Biomechanical Phenomena / genetics Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cholinesterase Inhibitors / pharmacology Disease Models, Animal Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism Gait Disorders, Neurologic / etiology* Gait Disorders, Neurologic / pathology Gait Disorders, Neurologic / therapy* Levamisole / pharmacology Longevity / drug effects Longevity / genetics Muscular Atrophy, Spinal / complications* Muscular Atrophy, Spinal / genetics Muscular Atrophy, Spinal / therapy Neuromuscular Junction / drug effects Neuromuscular Junction / pathology Pyridostigmine Bromide / pharmacology RNA Interference / physiology Signal Transduction / drug effects Signal Transduction / genetics Survival Analysis Survival of Motor Neuron 1 Protein / genetics gamma-Aminobutyric Acid / metabolism*
IF 3.544
Times Cited 2