Axon Degeneration: Too Much NMN Is Actually Bad?

Cohen, Michael S.

doi:10.1016/j.cub.2017.02.058

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…To date, expression of WLD S /NMNATs (which substitute for endogenous NMNAT2 loss) and SARM1 depletion are the most effective means to block the Wallerian pathway and preserve axons in mammals. There is still debate about how NMNAT2 loss leads to SARM1 activation but the rise in its substrate, NMN, appears to be important ( Di Stefano et al, 2015 , 2017 ; Loreto et al, 2015 ; Cohen, 2017 ; Zhao et al, 2019 ) as well as the fall in its product, NAD ( Gerdts et al, 2015 ; Sasaki et al, 2016 ; Essuman et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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

Loreto

Hill

Hewitt

et al. 2020

Neurobiology of Disease

105

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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 WLD S 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.

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Section: Introductionmentioning

confidence: 99%

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

Loreto

Hill

Hewitt

et al. 2020

Neurobiology of Disease

105

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SARM1 can be a potential therapeutic target for spinal cord injury

Botchway

Zhang

et al. 2022

Cell. Mol. Life Sci.

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

Loreto

Hill

Hewitt

et al. 2019

Preprint

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26Wallerian degeneration of physically injured axons involves a well-defined molecular 27 pathway linking loss of axonal survival factor NMNAT2 to activation of pro-28 degenerative protein SARM1. Manipulating the pathway through these proteins led to 29 the identification of non-axotomy insults causing axon degeneration by a Wallerian-30 like mechanism, including several involving mitochondrial impairment. Mitochondrial 31 dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth 32 disease, hereditary spastic paraplegia and other axonal disorders. However, whether 33 and how mitochondrial impairment activates Wallerian degeneration has remained 34 unclear. Here, we show that disruption of mitochondrial membrane potential leads to 35 axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-36to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint 37 of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 38 synthesis and reduced axonal transport. Expression of WLD S and Sarm1 deletion both 39 protect axons after mitochondrial uncoupling. Blocking the pathway also confers 40 neuroprotection and increases the lifespan of flies with Pink1 loss-of-function 41 mutation, which causes severe mitochondrial defects. These data indicate that 42 mitochondrial impairment replicates all the major steps of Wallerian degeneration, 43 placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology 44 in mitochondrial disorders. 45 RESULTS 101

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Axon Degeneration: Too Much NMN Is Actually Bad?

Abstract: The mechanism of axon degeneration is incompletely understood. A recent study demonstrates that transgenic expression of bacterial nicotinamide adenine mononucleotide (NMN) in zebrafish and mice, which decreases NMN levels by converting it to NaMN, protects against axon degeneration.

Cited by 4 publications

References 21 publications

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

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

SARM1 can be a potential therapeutic target for spinal cord injury

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

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