Mechanistic insights into an axon death pathway controlled by NAD-related metabolismTools Loreto, Andrea (2018) Mechanistic insights into an axon death pathway controlled by NAD-related metabolism. PhD thesis, University of Nottingham.
AbstractStudies of axon degeneration following an injury, known as Wallerian degeneration, and the axon-protective protein WLDs revealed a strong link between NAD metabolism and the mechanisms resulting in axonal destruction. Current knowledge indicates that the labile axonal NAD-synthesising enzyme NMNAT2 is essential for axonal survival. Its depletion, following an injury or its genetic removal, causes axon degeneration or defective axon growth. We recently proposed a key role for NAD-precursor NMN, which rapidly accumulates in transected nerves as a consequence of NMNAT2 depletion, in initiating axon degeneration after injury. Pharmacological and genetic reduction of NMN levels, by inhibition of NMN-synthesising enzyme NAMPT or expression of the bacterial NMN-scavenging enzyme NMN deamidase, robustly delays Wallerian degeneration. Recent evidence suggests that NMNAT2 and the pro- degenerative protein SARM1 cooperate in a core pathway regulating axon degeneration. It is important to fully understand the mechanism of Wallerian degeneration because related mechanisms could contribute to axon loss in several disease models, including peripheral neuropathies, Parkinson’s disease, multiple sclerosis and glaucoma.
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