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Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Citation

Clark, JA and Southam, KA and Blizzard, CA and King, AE and Dickson, TC, Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis, Journal of Chemical Neuroanatomy, 76, (Pt A) pp. 35-47. ISSN 0891-0618 (2016) [Refereed Article]

Copyright Statement

Copyright 2016 Elsevier B.V.

DOI: doi:10.1016/j.jchemneu.2016.03.003

Abstract

Degeneration of the distal axon and neuromuscular junction (NMJ) is considered a key and early feature of the pathology that accompanies motor neuron loss in people with amyotrophic lateral sclerosis (ALS). The mutant SOD1G93A mouse replicates many features of the disease, however the sequence of events resulting in degeneration of the neuromuscular circuitry remains unknown. Furthermore, despite widespread degenerative neuronal pathology throughout the spinal cord in this model, hindlimb motor function is lost before forelimb function. We investigated axons and NMJs in the hindlimb (gastrocnemius) and forelimb (extensor) muscles in the high copy number mutant SOD1G93AxYFP (yellow fluorescent protein) mouse. We found that distal axonal and NMJ alterations were present prior to previously reported functional symptom onset in this strain. Indeed, increased branch complexity as well as colocalisation between pre- and post-synaptic markers indicated widespread early axonal and NMJ alterations in the hindlimb. Immunohistochemical analysis demonstrated that the colocalisation of the scaffolding proteins nestin, LRP-4, dystrophin and rapsyn were diminished before post-synaptic receptors in the gastrocnemius, and the degree of loss differed between proteins. Analysis of the forelimb muscle revealed axonal and NMJ degeneration at a late, post symptomatic stage, as well as novel differences in NMJ morphology, with reduced complexity. Furthermore, post-synaptic scaffolding proteins were preserved in the forelimb compared with the hindlimb. Analysis of protein levels indicated an increase in LRP-4, dystrophin and rapsyn in post symptomatic skeletal muscle that may suggest ongoing attempts at repair. This study indicates that axonal and NMJ degeneration in the SOD1 model of ALS is a complex and evolving sequence of events. We provide evidence that YFP can detect morphological and plastic alterations in the SOD1G93A mouse, and that the pre- and post-synaptic integrity of the NMJ plays an important role in the pathogenic mechanisms of ALS.

Item Details

Item Type:Refereed Article
Keywords:neuromuscular junction, SOD1G93A, amyotrophic lateral sclerosis, distal 'dying back' degeneration, forelimb pathology
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurology and Neuromuscular Diseases
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Clark, JA (Mr Jayden Clark)
Author:Southam, KA (Dr Katherine Southam)
Author:Blizzard, CA (Dr Catherine Blizzard)
Author:King, AE (Associate Professor Anna King)
Author:Dickson, TC (Associate Professor Tracey Dickson)
ID Code:109202
Year Published:2016
Web of Science® Times Cited:5
Deposited By:Medicine (Discipline)
Deposited On:2016-06-01
Last Modified:2017-08-02
Downloads:0

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