NMNAT2 is a druggable target to drive neuronal NAD production

Tribble, James R., Jöe, Melissa, Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Otmani, Amin, Canovai, Alessio, Habchi, Baninia, Daskalakis, Evangelia, Chaleckis, Romanas, Loreto, Andrea, Gilley, Jonathan, Wheelock, Craig E., Jóhannesson, Gauti, Wong, Raymond C. B., Coleman, Michael P., Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and Williams, Pete A. 2024. NMNAT2 is a druggable target to drive neuronal NAD production. Nature Communications 15 (1) , 6256. 10.1038/s41467-024-50354-5

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Abstract

Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Additional Information:	An Author Correction to this article was published on 17 September 2024, this can be seen at https://doi.org/10.1038/s41467-024-52439-7 License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	26 July 2024
Date of Acceptance:	19 June 2024
Last Modified:	18 Sep 2024 09:32
URI:	https://orca.cardiff.ac.uk/id/eprint/170947

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