RRC ID 33660
Author McGown A, McDearmid JR, Panagiotaki N, Tong H, Al Mashhadi S, Redhead N, Lyon AN, Beattie CE, Shaw PJ, Ramesh TM.
Title Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model.
Journal Ann Neurol
Abstract OBJECTIVE:To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs.
METHODS:Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease.
RESULTS:We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response.
INTERPRETATION:The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action.
Volume 73(2)
Pages 246-58
Published 2013-2-1
DOI 10.1002/ana.23780
PMID 23281025
PMC PMC3608830
MeSH Amyotrophic Lateral Sclerosis / drug therapy Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / pathology Amyotrophic Lateral Sclerosis / physiopathology* Animals Animals, Genetically Modified Apomorphine / pharmacology Disease Models, Animal* Dopamine Agonists / pharmacology Genes, Reporter Glycine / physiology HSP72 Heat-Shock Proteins / genetics Humans Interneurons / drug effects Interneurons / pathology Interneurons / physiology* Mice Motor Neurons / drug effects Motor Neurons / pathology Motor Neurons / physiology Muscle, Skeletal / innervation NF-E2-Related Factor 2 / metabolism Neuromuscular Junction / pathology Neuromuscular Junction / physiopathology Neuroprotective Agents Patch-Clamp Techniques Riluzole / pharmacology Stress, Physiological / drug effects Stress, Physiological / physiology Superoxide Dismutase / genetics* Superoxide Dismutase / metabolism Superoxide Dismutase-1 Zebrafish* Zebrafish Proteins / metabolism
IF 9.037
Times Cited 53
Zebrafish Tg(isl1:GFP)/rw0