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NMNAT2 is a druggable target to drive neuronal NAD production

Author

Listed:
  • 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
    University of Pisa)

  • Baninia Habchi

    (Karolinska Institute
    Karolinska University Hospital
    Aix Marseille University)

  • Evangelia Daskalakis

    (Karolinska Institute
    Karolinska University Hospital)

  • Romanas Chaleckis

    (Karolinska Institute
    Karolinska University Hospital
    Gunma University)

  • Andrea Loreto

    (Department of Clinical Neurosciences; University of Cambridge
    The University of Sydney)

  • Jonathan Gilley

    (Department of Clinical Neurosciences; University of Cambridge)

  • Craig E. Wheelock

    (Karolinska Institute
    Karolinska University Hospital)

  • Gauti Jóhannesson

    (Umeå University
    Umeå University)

  • Raymond C. B. Wong

    (Royal Victorian Eye and Ear Hospital
    University of Melbourne)

  • Michael P. Coleman

    (Department of Clinical Neurosciences; University of Cambridge)

  • Andrea Brancale

    (School of Pharmacy and Pharmaceutical Sciences; Cardiff University
    Vysoká škola chemicko-technologická v Praze)

  • Pete A. Williams

    (St. Erik Eye Hospital; Karolinska Institutet)

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.

Suggested Citation

  • James R. Tribble & Melissa Jöe & Carmine Varricchio & Amin Otmani & Alessio Canovai & Baninia Habchi & Evangelia Daskalakis & Romanas Chaleckis & Andrea Loreto & Jonathan Gilley & Craig E. Wheelock & , 2024. "NMNAT2 is a druggable target to drive neuronal NAD production," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50354-5
    DOI: 10.1038/s41467-024-50354-5
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    References listed on IDEAS

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    1. Pradeep Gautam & Kiyofumi Hamashima & Ying Chen & Yingying Zeng & Bar Makovoz & Bhav Harshad Parikh & Hsin Yee Lee & Katherine Anne Lau & Xinyi Su & Raymond C. B. Wong & Woon-Khiong Chan & Hu Li & Tim, 2021. "Multi-species single-cell transcriptomic analysis of ocular compartment regulons," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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