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Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is essentia...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233423/ https://www.ncbi.nlm.nih.gov/pubmed/34172715 http://dx.doi.org/10.1038/s41419-021-03926-y |
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author | Yu, Yizhou Fedele, Giorgio Celardo, Ivana Loh, Samantha H. Y. Martins, L. Miguel |
author_facet | Yu, Yizhou Fedele, Giorgio Celardo, Ivana Loh, Samantha H. Y. Martins, L. Miguel |
author_sort | Yu, Yizhou |
collection | PubMed |
description | Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD(+)-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD(+) protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD(+) or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD(+) by either vitamin B supplements or the inhibition of NAD(+)-dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease. |
format | Online Article Text |
id | pubmed-8233423 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82334232021-07-09 Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease Yu, Yizhou Fedele, Giorgio Celardo, Ivana Loh, Samantha H. Y. Martins, L. Miguel Cell Death Dis Article Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD(+)-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD(+) protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD(+) or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD(+) by either vitamin B supplements or the inhibition of NAD(+)-dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease. Nature Publishing Group UK 2021-06-25 /pmc/articles/PMC8233423/ /pubmed/34172715 http://dx.doi.org/10.1038/s41419-021-03926-y Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yu, Yizhou Fedele, Giorgio Celardo, Ivana Loh, Samantha H. Y. Martins, L. Miguel Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title | Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title_full | Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title_fullStr | Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title_full_unstemmed | Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title_short | Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease |
title_sort | parp mutations protect from mitochondrial toxicity in alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233423/ https://www.ncbi.nlm.nih.gov/pubmed/34172715 http://dx.doi.org/10.1038/s41419-021-03926-y |
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