Öppna denna publikation i ny flik eller fönster >>Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Biology, University of Pisa, Pisa, Italy.
Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France.
Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan.
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; School of Medical Sciences and Save Sight Institute, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, NSW, Sydney, Australia.
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, University of Melbourne, VIC, East Melbourne, Australia.
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, Cardiff, United Kingdom; Vysoká škola chemicko-technologická v Praze, Prague, Czech Republic.
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
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2024 (Engelska)Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikel-id 6256Artikel i tidskrift (Refereegranskat) Published
Abstract [en]
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.
Ort, förlag, år, upplaga, sidor
Springer Nature, 2024
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-228124 (URN)10.1038/s41467-024-50354-5 (DOI)001276353800023 ()39048544 (PubMedID)2-s2.0-85199429355 (Scopus ID)
Forskningsfinansiär
ÖgonfondenKarolinska Institutets ForskningsstiftelseLoo och Hans Ostermans Stiftelse för medicinsk forskningStiftelsen Lars Hiertas MinneKnut och Alice Wallenbergs StiftelseRegion VästerbottenKarolinska InstitutetVetenskapsrådet, 2018-02124Vetenskapsrådet, 2022-00799Stiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadadePetrus och Augusta Hedlunds Stiftelse
Anmärkning
Errata:
Tribble, J.R., Jöe, M., Varricchio, C. et al. Author Correction: NMNAT2 is a druggable target to drive neuronal NAD production. Nat Commun 15, 8143 (2024). https://doi.org/10.1038/s41467-024-52439-7
2024-08-052024-08-052025-04-24Bibliografiskt granskad