| RRC ID |
59423
|
| 著者 |
Wu CY, Gagnon DA, Sardin JS, Barot U, Telenson A, Arratia PE, Kalb RG.
|
| タイトル |
Enhancing GABAergic Transmission Improves Locomotion in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.
|
| ジャーナル |
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.
|
| 巻・号 |
5(6)
|
| 公開日 |
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
|
| 引用数 |
2
|
| リソース情報 |
| 線虫 |
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