NMNAT2 is a druggable target to drive neuronal NAD production

James R. Tribble, Melissa Jöe, Carmine Varricchio, Amin Otmani, Alessio Canovai, Baninia Habchi, Evangelia Daskalakis, Romanas Chaleckis, Andrea Loreto, Jonathan Gilley, Craig E. Wheelock, Gauti Jóhannesson, Raymond C. B. Wong, Michael P. Coleman, Andrea Brancale and Pete A. Williams ()
Additional contact information
James R. Tribble: St. Erik Eye Hospital; Karolinska Institutet
Melissa Jöe: St. Erik Eye Hospital; Karolinska Institutet
Carmine Varricchio: School of Pharmacy and Pharmaceutical Sciences; Cardiff University
Amin Otmani: St. Erik Eye Hospital; Karolinska Institutet
Alessio Canovai: St. Erik Eye Hospital; Karolinska Institutet
Baninia Habchi: Karolinska Institute
Evangelia Daskalakis: Karolinska Institute
Romanas Chaleckis: Karolinska Institute
Andrea Loreto: Department of Clinical Neurosciences; University of Cambridge
Jonathan Gilley: Department of Clinical Neurosciences; University of Cambridge
Craig E. Wheelock: Karolinska Institute
Gauti Jóhannesson: Umeå University
Raymond C. B. Wong: Royal Victorian Eye and Ear Hospital
Michael P. Coleman: Department of Clinical Neurosciences; University of Cambridge
Andrea Brancale: School of Pharmacy and Pharmaceutical Sciences; Cardiff University
Pete A. Williams: St. Erik Eye Hospital; Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50354-5

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