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Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress

Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protecti...

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Autores principales: Ruan, Kai, Zhu, Yi, Li, Chong, Brazill, Jennifer M., Zhai, R. Grace
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674693/
https://www.ncbi.nlm.nih.gov/pubmed/26616331
http://dx.doi.org/10.1038/ncomms10057
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author Ruan, Kai
Zhu, Yi
Li, Chong
Brazill, Jennifer M.
Zhai, R. Grace
author_facet Ruan, Kai
Zhu, Yi
Li, Chong
Brazill, Jennifer M.
Zhai, R. Grace
author_sort Ruan, Kai
collection PubMed
description Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection.
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spelling pubmed-46746932015-12-21 Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress Ruan, Kai Zhu, Yi Li, Chong Brazill, Jennifer M. Zhai, R. Grace Nat Commun Article Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection. Nature Pub. Group 2015-11-30 /pmc/articles/PMC4674693/ /pubmed/26616331 http://dx.doi.org/10.1038/ncomms10057 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ruan, Kai
Zhu, Yi
Li, Chong
Brazill, Jennifer M.
Zhai, R. Grace
Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title_full Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title_fullStr Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title_full_unstemmed Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title_short Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
title_sort alternative splicing of drosophila nmnat functions as a switch to enhance neuroprotection under stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674693/
https://www.ncbi.nlm.nih.gov/pubmed/26616331
http://dx.doi.org/10.1038/ncomms10057
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