Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice.

Autor: Kline RA; Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, EH25 9RG, UK., Dissanayake KN; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK; Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK., Hurtado ML; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, EH25 9RG, UK., Martínez NW; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile., Ahl A; Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK., Mole AJ; Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK., Lamont DJ; Fingerprints Proteomics Facility, Dundee University, Dundee DD1 4HN, United Kingdom., Court FA; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile; The Buck Institute for Research on Aging, Novato, CA, United States., Ribchester RR; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK; Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK., Wishart TM; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, EH25 9RG, UK., Murray LM; Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK. Electronic address: Lyndsay.Murray@ed.ac.uk.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2019 Oct; Vol. 130, pp. 104496. Date of Electronic Publication: 2019 Jun 06.
DOI: 10.1016/j.nbd.2019.104496
Abstrakt: Neurodegenerative and neuromuscular disorders can manifest throughout the lifespan of an individual, from infant to elderly individuals. Axonal and synaptic degeneration are early and critical elements of nearly all human neurodegenerative diseases and neural injury, however the molecular mechanisms which regulate this process are yet to be fully elucidated. Furthermore, how the molecular mechanisms governing degeneration are impacted by the age of the individual is poorly understood. Interestingly, in mice which are under 3 weeks of age, the degeneration of axons and synapses following hypoxic or traumatic injury is significantly slower. This process, known as Wallerian degeneration (WD), is a molecularly and morphologically distinct subtype of neurodegeneration by which axons and synapses undergo distinct fragmentation and death following a range of stimuli. In this study, we first use an ex-vivo model of axon injury to confirm the significant delay in WD in neonatal mice. We apply tandem mass-tagging quantitative proteomics to profile both nerve and muscle between P12 and P24 inclusive. Application of unbiased in silico workflows to relevant protein identifications highlights a steady elevation in oxidative phosphorylation cascades corresponding to the accelerated degeneration rate. We demonstrate that inhibition of Complex I prevents the axotomy-induced rise in reactive oxygen species and protects axons following injury. Furthermore, we reveal that pharmacological activation of oxidative phosphorylation significantly accelerates degeneration at the neuromuscular junction in neonatal mice. In summary, we reveal dramatic changes in the neuromuscular proteome during post-natal maturation of the neuromuscular system, and demonstrate that endogenous dynamics in mitochondrial bioenergetics during this time window have a functional impact upon regulating the stability of the neuromuscular system.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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