Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice
| Autor: | Kosala N. Dissanayake, Nicolas W. Martinez, Felipe A. Court, Douglas J. Lamont, Alannah J. Mole, Richard R. Ribchester, Lyndsay M. Murray, Rachel A. Kline, Thomas M. Wishart, Maria del carmen Llavero hurtado, Alexander Ahl |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
0301 basic medicine ETC Electron Transport Chain Wallerian degeneration MPS Mammalian Physiological Saline Bioenergetics P Post Natal Day Degeneration (medical) 2H3 Neurofilament Mitochondrion DRG Dorsal Root Ganglion Oxidative Phosphorylation Wallerian WD Wallerian Degeneration Mice Neonate 0302 clinical medicine Axon TMT Tandem Mass Tagging Neurodegeneration ROS Reaction Oxygen Species Mitochondria medicine.anatomical_structure Neurology Axon degeneration Neuromuscular Junction AMPK Adenosine Monophosphate Kinase Oxidative phosphorylation Biology Article Neuromuscular junction lcsh:RC321-571 03 medical and health sciences medicine Animals lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry SV2 Synaptic Vesicle Protein 2 IPA Ingenuity Pathway Analysis OXPHOS Oxidative Phosphorylation NMJ Neuromuscular Junction TEAB Tetraethylammonium Bromide NMJ QFWB Quantitative Fluorescent Western Blotting DHE Dihydroethidium ELISA Enzyme Link Immuno medicine.disease Mice Inbred C57BL TMT-QMS Tandem-Mass Tagging Quantitative Mass Spectrometry 030104 developmental biology Animals Newborn Wallerian Degeneration Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Kline, R, Dissanayake, K, Llavero hurtado, M D C, Martínez, N W, Ahl, A, Mole, A J, Lamont, D J, Court, F A, Ribchester, R, Wishart, T & Murray, L 2019, ' Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice. ', Neurobiology of disease, vol. 130, 104496 . https://doi.org/10.1016/j.nbd.2019.104496 Neurobiology of Disease Neurobiology of Disease, Vol 130, Iss, Pp 104496-(2019) |
| Popis: | 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. Graphical abstract Unlabelled Image Highlights • There is a decrease in the rate of injury induced Wallerian degeneration in motor axons aged P24. • There is a continuous increase in oxidative phosphorylation proteins from P12 to P24 in lumbrical muscle and tibial nerve. • Inhibition of complex I prevents axon degeneration following injury, and prevents the rise in reactive oxygen species. • Pharmacological activation of oxidative phosphorylation accelerates axonal and synaptic degeneration in neonatal mice. • Pharmacological inhibition of complex 1 protects axons from injury induced degeneration. |
| Databáze: | OpenAIRE |
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