Imperial College London
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ProfessorHectorKeun

Faculty of Medicine, Department of Surgery & Cancer

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 3161h.keun

 
 
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Location

 

officesInstitute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Allen:2019:brain/awy353,
author = {Allen, SP and Hall, B and Castelli, LM and Francis, L and Woof, R and Siskos, AP and Kouloura, E and Gray, E and Thompson, AG and Talbot, K and Higginbottom, A and Myszczynska, M and Allen, CF and Stopford, MJ and Hemingway, J and Bauer, CS and Webster, CP and De, Vos KJ and Turner, MR and Keun, HC and Hautbergue, GM and Ferraiuolo, L and Shaw, PJ},
doi = {brain/awy353},
journal = {Brain},
pages = {586--605},
title = {Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis},
url = {http://dx.doi.org/10.1093/brain/awy353},
volume = {142},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Allen,SP
AU  - Hall,B
AU  - Castelli,LM
AU  - Francis,L
AU  - Woof,R
AU  - Siskos,AP
AU  - Kouloura,E
AU  - Gray,E
AU  - Thompson,AG
AU  - Talbot,K
AU  - Higginbottom,A
AU  - Myszczynska,M
AU  - Allen,CF
AU  - Stopford,MJ
AU  - Hemingway,J
AU  - Bauer,CS
AU  - Webster,CP
AU  - De,Vos KJ
AU  - Turner,MR
AU  - Keun,HC
AU  - Hautbergue,GM
AU  - Ferraiuolo,L
AU  - Shaw,PJ
DO  - brain/awy353
EP  - 605
PY  - 2019///
SN  - 1460-2156
SP  - 586
TI  - Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis
T2  - Brain
UR  - http://dx.doi.org/10.1093/brain/awy353
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30698736
UR  - http://hdl.handle.net/10044/1/67685
VL  - 142
ER  -
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