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Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death

Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD(+) biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight...

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Autores principales: Wang, Xiaowan, Zhang, Qiao, Bao, Ruisi, Zhang, Nannan, Wang, Yingzhen, Polo-Parada, Luis, Tarim, Andrew, Alemifar, Aidan, Han, Xianlin, Wilkins, Heather M., Swerdlow, Russell H., Wang, Xinglong, Ding, Shinghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021762/
https://www.ncbi.nlm.nih.gov/pubmed/28854367
http://dx.doi.org/10.1016/j.celrep.2017.08.022
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author Wang, Xiaowan
Zhang, Qiao
Bao, Ruisi
Zhang, Nannan
Wang, Yingzhen
Polo-Parada, Luis
Tarim, Andrew
Alemifar, Aidan
Han, Xianlin
Wilkins, Heather M.
Swerdlow, Russell H.
Wang, Xinglong
Ding, Shinghua
author_facet Wang, Xiaowan
Zhang, Qiao
Bao, Ruisi
Zhang, Nannan
Wang, Yingzhen
Polo-Parada, Luis
Tarim, Andrew
Alemifar, Aidan
Han, Xianlin
Wilkins, Heather M.
Swerdlow, Russell H.
Wang, Xinglong
Ding, Shinghua
author_sort Wang, Xiaowan
collection PubMed
description Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD(+) biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD(+) biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.
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spelling pubmed-60217622018-08-29 Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death Wang, Xiaowan Zhang, Qiao Bao, Ruisi Zhang, Nannan Wang, Yingzhen Polo-Parada, Luis Tarim, Andrew Alemifar, Aidan Han, Xianlin Wilkins, Heather M. Swerdlow, Russell H. Wang, Xinglong Ding, Shinghua Cell Rep Article Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD(+) biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD(+) biosynthesis pathway is a potential therapeutic target for degenerative MN diseases. 2017-08-29 /pmc/articles/PMC6021762/ /pubmed/28854367 http://dx.doi.org/10.1016/j.celrep.2017.08.022 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Wang, Xiaowan
Zhang, Qiao
Bao, Ruisi
Zhang, Nannan
Wang, Yingzhen
Polo-Parada, Luis
Tarim, Andrew
Alemifar, Aidan
Han, Xianlin
Wilkins, Heather M.
Swerdlow, Russell H.
Wang, Xinglong
Ding, Shinghua
Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title_full Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title_fullStr Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title_full_unstemmed Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title_short Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death
title_sort deletion of nampt in projection neurons of adult mice leads to motor dysfunction, neurodegeneration, and death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021762/
https://www.ncbi.nlm.nih.gov/pubmed/28854367
http://dx.doi.org/10.1016/j.celrep.2017.08.022
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