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Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis

Title: Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis
Authors: Allen, SP
Hall, B
Castelli, LM
Francis, L
Woof, R
Siskos, AP
Kouloura, E
Gray, E
Thompson, AG
Talbot, K
Higginbottom, A
Myszczynska, M
Allen, CF
Stopford, MJ
Hemingway, J
Bauer, CS
Webster, CP
De Vos, KJ
Turner, MR
Keun, HC
Hautbergue, GM
Ferraiuolo, L
Shaw, PJ
Item Type: Journal Article
Abstract: As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or rerouting catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we used a novel phenotypic metabolic array. We profiled fibroblasts and induced neuronal progenitor-derived human induced astrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach shows for the first time that C9orf72 human induced astrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in induced astrocytes from sporadic patients. Patient-derived induced astrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control induced astrocytes led to increased motor neuron toxicity in co-cultures, similar to the levels observed with patient derived induced astrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with induced astrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis.
Issue Date: 1-Mar-2019
Date of Acceptance: 22-Nov-2018
URI: http://hdl.handle.net/10044/1/67685
DOI: https://dx.doi.org/10.1093/brain/awy353
ISSN: 1460-2156
Publisher: Oxford University Press (OUP)
Start Page: 586
End Page: 605
Journal / Book Title: Brain
Volume: 142
Issue: 3
Copyright Statement: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permitsnon-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 259867
Keywords: C9orf72
ALS
metabolism: inosine: adenosine deaminase
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Neurology & Neurosurgery
Publication Status: Published
Conference Place: England
Online Publication Date: 2019-01-28
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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