NMNAT2 is a druggable target to drive neuronal NAD production
Jazyk angličtina Země Anglie, Velká Británie Médium electronic
Typ dokumentu časopisecké články
Grantová podpora
Wellcome Trust - United Kingdom
2018-02124
Vetenskapsrådet (Swedish Research Council)
2022-00799
Vetenskapsrådet (Swedish Research Council)
PubMed
39048544
PubMed Central
PMC11269627
DOI
10.1038/s41467-024-50354-5
PII: 10.1038/s41467-024-50354-5
Knihovny.cz E-zdroje
- MeSH
- genetická terapie metody MeSH
- katechin * analogy a deriváty farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NAD * metabolismus MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus genetika MeSH
- neurony * metabolismus účinky léků MeSH
- neuroprotektivní látky * farmakologie MeSH
- nikotinamidnukleotidadenylyltransferasa * metabolismus genetika MeSH
- retina metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- epigallocatechin gallate MeSH Prohlížeč
- katechin * MeSH
- NAD * MeSH
- neuroprotektivní látky * MeSH
- nikotinamidnukleotidadenylyltransferasa * MeSH
- NMNAT2 protein, human MeSH Prohlížeč
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.
C2VN INRAE INSERM Aix Marseille University 13007 Marseille France
Centre for Eye Research Australia Royal Victorian Eye and Ear Hospital East Melbourne Australia
Department of Biology University of Pisa 56127 Pisa Italy
Department of Clinical Sciences Ophthalmology Umeå University 901 85 Umeå Sweden
Department of Respiratory Medicine and Allergy Karolinska University Hospital Stockholm Sweden
Gunma Initiative for Advanced Research Gunma University Maebashi Japan
Ophthalmology Department of Surgery University of Melbourne East Melbourne Victoria Australia
School of Pharmacy and Pharmaceutical Sciences; Cardiff University Cardiff Wales UK
Vysoká škola chemicko technologická Praha Prague Czech Republic
Wallenberg Centre of Molecular Medicine Umeå University 901 85 Umeå Sweden
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