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NMNAT2 is a druggable target to drive neuronal NAD production

JR. Tribble, M. Jöe, C. Varricchio, A. Otmani, A. Canovai, B. Habchi, E. Daskalakis, R. Chaleckis, A. Loreto, J. Gilley, CE. Wheelock, G. Jóhannesson, RCB. Wong, MP. Coleman, A. Brancale, PA. Williams

. 2024 ; 15 (1) : 6256. [pub] 20240724

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019687

Grantová podpora
Wellcome Trust - United Kingdom
2018-02124 Vetenskapsrådet (Swedish Research Council)
2022-00799 Vetenskapsrådet (Swedish Research Council)

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.

Citace poskytuje Crossref.org

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$a NMNAT2 is a druggable target to drive neuronal NAD production / $c JR. Tribble, M. Jöe, C. Varricchio, A. Otmani, A. Canovai, B. Habchi, E. Daskalakis, R. Chaleckis, A. Loreto, J. Gilley, CE. Wheelock, G. Jóhannesson, RCB. Wong, MP. Coleman, A. Brancale, PA. Williams
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$a 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.
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$a Jöe, Melissa $u Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital; Karolinska Institutet, Stockholm, Sweden $1 https://orcid.org/0000000185164706
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$a Varricchio, Carmine $u School of Pharmacy and Pharmaceutical Sciences; Cardiff University, Cardiff, Wales, UK
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$a Otmani, Amin $u Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital; Karolinska Institutet, Stockholm, Sweden
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$a Canovai, Alessio $u Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital; Karolinska Institutet, Stockholm, Sweden $u Department of Biology, University of Pisa, 56127, Pisa, Italy $1 https://orcid.org/0009000792294710
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$a Habchi, Baninia $u Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden $u Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden $u C2VN, INRAE, INSERM, Aix Marseille University, 13007, Marseille, France $1 https://orcid.org/000000019705167X
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$a Daskalakis, Evangelia $u Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden $u Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
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$a Chaleckis, Romanas $u Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden $u Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden $u Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan $1 https://orcid.org/0000000180421005
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$a Loreto, Andrea $u John van Geest Centre for Brain Repair, Department of Clinical Neurosciences; University of Cambridge, Cambridge, UK $u School of Medical Sciences and Save Sight Institute, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia $1 https://orcid.org/0000000165356436
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$a Gilley, Jonathan $u John van Geest Centre for Brain Repair, Department of Clinical Neurosciences; University of Cambridge, Cambridge, UK
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$a Wheelock, Craig E $u Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden $u Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden $1 https://orcid.org/0000000281130653
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$a Jóhannesson, Gauti $u Department of Clinical Sciences, Ophthalmology, Umeå University, 901 85, Umeå, Sweden $u Wallenberg Centre of Molecular Medicine, Umeå University, 901 85, Umeå, Sweden
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$a Wong, Raymond C B $u Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia $u Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Victoria, Australia $1 https://orcid.org/0000000280929455 $7 ntk20211128090
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$a Coleman, Michael P $u John van Geest Centre for Brain Repair, Department of Clinical Neurosciences; University of Cambridge, Cambridge, UK $1 https://orcid.org/000000029354532X
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$a Williams, Pete A $u Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital; Karolinska Institutet, Stockholm, Sweden. pete.williams@ki.se $1 https://orcid.org/0000000161948397
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