The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.

Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly...

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Main Authors: Xin Xiong, Yan Hao, Kan Sun, Jiaxing Li, Xia Li, Bibhudatta Mishra, Pushpanjali Soppina, Chunlai Wu, Richard I Hume, Catherine A Collins
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS Biology
Online Access:http://europepmc.org/articles/PMC3514318?pdf=render
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spelling doaj-6471351081554ec7bb481ccd5535921e2021-07-02T04:02:43ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852012-01-011012e100144010.1371/journal.pbio.1001440The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.Xin XiongYan HaoKan SunJiaxing LiXia LiBibhudatta MishraPushpanjali SoppinaChunlai WuRichard I HumeCatherine A CollinsAxonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly inhibit Wallerian degeneration in multiple neuron types and developmental stages. This new phenotype is mediated by a new downstream target of Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat), which acts in parallel to a previously known target of Hiw, the Wallenda dileucine zipper kinase (Wnd/DLK) MAPKKK. Hiw promotes a rapid disappearance of Nmnat protein in the distal stump after injury. An increased level of Nmnat protein in hiw mutants is both required and sufficient to inhibit degeneration. Ectopically expressed mouse Nmnat2 is also subject to regulation by Hiw in distal axons and synapses. These findings implicate an important role for endogenous Nmnat and its regulation, via a conserved mechanism, in the initiation of axonal degeneration. Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury.http://europepmc.org/articles/PMC3514318?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Xin Xiong
Yan Hao
Kan Sun
Jiaxing Li
Xia Li
Bibhudatta Mishra
Pushpanjali Soppina
Chunlai Wu
Richard I Hume
Catherine A Collins
spellingShingle Xin Xiong
Yan Hao
Kan Sun
Jiaxing Li
Xia Li
Bibhudatta Mishra
Pushpanjali Soppina
Chunlai Wu
Richard I Hume
Catherine A Collins
The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
PLoS Biology
author_facet Xin Xiong
Yan Hao
Kan Sun
Jiaxing Li
Xia Li
Bibhudatta Mishra
Pushpanjali Soppina
Chunlai Wu
Richard I Hume
Catherine A Collins
author_sort Xin Xiong
title The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
title_short The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
title_full The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
title_fullStr The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
title_full_unstemmed The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
title_sort highwire ubiquitin ligase promotes axonal degeneration by tuning levels of nmnat protein.
publisher Public Library of Science (PLoS)
series PLoS Biology
issn 1544-9173
1545-7885
publishDate 2012-01-01
description Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly inhibit Wallerian degeneration in multiple neuron types and developmental stages. This new phenotype is mediated by a new downstream target of Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat), which acts in parallel to a previously known target of Hiw, the Wallenda dileucine zipper kinase (Wnd/DLK) MAPKKK. Hiw promotes a rapid disappearance of Nmnat protein in the distal stump after injury. An increased level of Nmnat protein in hiw mutants is both required and sufficient to inhibit degeneration. Ectopically expressed mouse Nmnat2 is also subject to regulation by Hiw in distal axons and synapses. These findings implicate an important role for endogenous Nmnat and its regulation, via a conserved mechanism, in the initiation of axonal degeneration. Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury.
url http://europepmc.org/articles/PMC3514318?pdf=render
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