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Neurobiol Dis. 2019 Nov 15;134:104678. doi: 10.1016/j.nbd.2019.104678. [Epub ahead of print]

Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration.

Author information

1
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK. Electronic address: al850@cam.ac.uk.
2
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK.
3
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
4
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
5
School of Life Sciences, Medical School, University of Nottingham, NG7 2UH Nottingham, UK.
6
School of Life Sciences, Medical School, University of Nottingham, NG7 2UH Nottingham, UK. Electronic address: f.dajas-bailador@nottingham.ac.uk.
7
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK. Electronic address: mc469@cam.ac.uk.

Abstract

Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

KEYWORDS:

Axon degeneration; Mitochondrial dysfunction; NMNAT2; Parkinson's disease; Pink1; SARM1; Wallerian degeneration

PMID:
31740269
DOI:
10.1016/j.nbd.2019.104678
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