Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Neurobiology of disease, 2019-10, Vol.130, p.104496, Article 104496

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •There is a decrease in the rate of injury induced Wallerian degeneration in motor axons aged <P12 vs >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.