Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis - vulnerability of lower motor neurons to proximal excitotoxicity

Disease Models & Mechanisms
Catherine A BlizzardTracey C Dickson

Abstract

There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degenerati...Continue Reading

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Citations

Mar 15, 2016·Frontiers in Neuroscience·Catherine A BlizzardTracey C Dickson
Oct 31, 2015·Neuropharmacology·Cinzia VolontéSusanna Amadio
Sep 30, 2016·Frontiers in Cellular Neuroscience·Jayden A ClarkTracey C Dickson
Jan 31, 2018·Neuropathology and Applied Neurobiology·J A ClarkT C Dickson
Aug 10, 2017·Molecular Medicine Reports·Ting ZhouMichael Namaka
Mar 24, 2020·Brain : a Journal of Neurology·C Sahara KhademullahMelanie A Woodin
Jul 13, 2020·Journal of Neurochemistry·Courtney M ClarkTracey C Dickson
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Jan 10, 2019·Frontiers in Bioengineering and Biotechnology·Maider Badiola-MateosJosep Samitier
Apr 19, 2018·Neurology Research International·Anna Caroline Marques BragaMamede de Carvalho

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Methods Mentioned

BETA
Confocal microscopy

Software Mentioned

GraphPad Prism
Photoshop
ImageJ
Zen

Related Concepts

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