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

Rachel A. Kline, Kosala N. Dissanayake, Maica Llavero Hurtado, Nicolás W. Martínez, Alexander Ahl, Alannah J. Mole, Douglas J. Lamont, Felipe A. Court, Richard R. Ribchester, Thomas M. Wishart, Lyndsay M. Murray (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Article number104496
Pages (from-to)1-16
Number of pages16
JournalNeurobiology of Disease
Volume130
Early online date6 Jun 2019
DOIs
Publication statusPublished - 1 Oct 2019

Fingerprint

Wallerian Degeneration
Energy Metabolism
Axons
Oxidative Phosphorylation
Wounds and Injuries
Neurodegenerative Diseases
Synapses
Mitochondrial Dynamics
Axotomy
Workflow
Neuromuscular Junction
Proteome
Computer Simulation
Proteomics
Reactive Oxygen Species
Pharmacology
Muscles
Proteins

Keywords

  • Axon degeneration
  • Mitochondria
  • NMJ
  • Neonate
  • Neurodegeneration
  • Neuromuscular junction
  • Proteomics
  • Wallerian

Cite this

Kline, R. A., Dissanayake, K. N., Hurtado, M. L., Martínez, N. W., Ahl, A., Mole, A. J., ... Murray, L. M. (2019). Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice. Neurobiology of Disease, 130, 1-16. [104496]. https://doi.org/10.1016/j.nbd.2019.104496
Kline, Rachel A. ; Dissanayake, Kosala N. ; Hurtado, Maica Llavero ; Martínez, Nicolás W. ; Ahl, Alexander ; Mole, Alannah J. ; Lamont, Douglas J. ; Court, Felipe A. ; Ribchester, Richard R. ; Wishart, Thomas M. ; Murray, Lyndsay M. / Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice. In: Neurobiology of Disease. 2019 ; Vol. 130. pp. 1-16.
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abstract = "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.",
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Kline, RA, Dissanayake, KN, Hurtado, ML, Martínez, NW, Ahl, A, Mole, AJ, Lamont, DJ, Court, FA, Ribchester, RR, Wishart, TM & Murray, LM 2019, 'Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice', Neurobiology of Disease, vol. 130, 104496, pp. 1-16. https://doi.org/10.1016/j.nbd.2019.104496

Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice. / Kline, Rachel A.; Dissanayake, Kosala N.; Hurtado, Maica Llavero; Martínez, Nicolás W.; Ahl, Alexander; Mole, Alannah J.; Lamont, Douglas J.; Court, Felipe A.; Ribchester, Richard R.; Wishart, Thomas M.; Murray, Lyndsay M. (Lead / Corresponding author).

In: Neurobiology of Disease, Vol. 130, 104496, 01.10.2019, p. 1-16.

Research output: Contribution to journalArticle

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AU - Kline, Rachel A.

AU - Dissanayake, Kosala N.

AU - Hurtado, Maica Llavero

AU - Martínez, Nicolás W.

AU - Ahl, Alexander

AU - Mole, Alannah J.

AU - Lamont, Douglas J.

AU - Court, Felipe A.

AU - Ribchester, Richard R.

AU - Wishart, Thomas M.

AU - Murray, Lyndsay M.

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

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