Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model
Version of Record online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 2, pages 246–258, February 2013
How to Cite
McGown, A., McDearmid, J. R., Panagiotaki, N., Tong, H., Al Mashhadi, S., Redhead, N., Lyon, A. N., Beattie, C. E., Shaw, P. J. and Ramesh, T. M. (2013), Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model. Ann Neurol., 73: 246–258. doi: 10.1002/ana.23780
- Issue online: 22 MAR 2013
- Version of Record online: 31 DEC 2012
- Accepted manuscript online: 1 OCT 2012 06:05AM EST
- Manuscript Accepted: 24 SEP 2012
- Manuscript Revised: 4 SEP 2012
- Manuscript Received: 20 APR 2012
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.
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.
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.
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. ANN NEUROL 2013;73:246–258