Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301512 |
| _version_ | 1819120115023609856 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Rachel A. Kline |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T06:15:32Z |
| format | Article |
| id | doaj.art-d7943619d6c0470097d6e53fe51e0db3 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:15:32Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d7943619d6c0470097d6e53fe51e0db32022-12-21T18:36:06ZengElsevierNeurobiology of Disease1095-953X2019-10-01130104496Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal miceRachel A. Kline0Kosala N. Dissanayake1Maica Llavero Hurtado2Nicolás W. Martínez3Alexander Ahl4Alannah J. Mole5Douglas J. Lamont6Felipe A. Court7Richard R. Ribchester8Thomas M. Wishart9Lyndsay M. Murray10Centre 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, UKEuan 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, UKEuan 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, UKCenter for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, ChileCentre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UKCentre 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, UKFingerprints Proteomics Facility, Dundee University, Dundee DD1 4HN, United KingdomCenter 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 StatesEuan 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, UKEuan 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, UKCentre 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; Corresponding author at: College of Medicine & Veterinary Medicine, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh EH8 9XD, UK.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.http://www.sciencedirect.com/science/article/pii/S0969996119301512NeurodegenerationWallerianNeonateAxon degenerationNeuromuscular junctionNMJ |
| spellingShingle | 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 Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice Neurobiology of Disease Neurodegeneration Wallerian Neonate Axon degeneration Neuromuscular junction NMJ |
| title | Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice |
| title_full | Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice |
| title_fullStr | Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice |
| title_full_unstemmed | Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice |
| title_short | Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice |
| title_sort | altered mitochondrial bioenergetics are responsible for the delay in wallerian degeneration observed in neonatal mice |
| topic | Neurodegeneration Wallerian Neonate Axon degeneration Neuromuscular junction NMJ |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301512 |
| work_keys_str_mv | AT rachelakline alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT kosalandissanayake alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT maicallaverohurtado alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT nicolaswmartinez alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT alexanderahl alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT alannahjmole alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT douglasjlamont alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT felipeacourt alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT richardrribchester alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT thomasmwishart alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice AT lyndsaymmurray alteredmitochondrialbioenergeticsareresponsibleforthedelayinwalleriandegenerationobservedinneonatalmice |