Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons.
The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degener...
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2010
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oai:doaj.org-article:632fc2e9aedc4d568fd9d42964dccb812021-11-25T05:34:23ZEndogenous Nmnat2 is an essential survival factor for maintenance of healthy axons.1544-91731545-788510.1371/journal.pbio.1000300https://doaj.org/article/632fc2e9aedc4d568fd9d42964dccb812010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20126265/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degeneration of uninjured axons which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld(S) neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld(S) does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld(S) protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.Jonathan GilleyMichael P ColemanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 1, p e1000300 (2010) |
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Biology (General) QH301-705.5 Jonathan Gilley Michael P Coleman Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
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The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degeneration of uninjured axons which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld(S) neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld(S) does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld(S) protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders. |
format |
article |
author |
Jonathan Gilley Michael P Coleman |
author_facet |
Jonathan Gilley Michael P Coleman |
author_sort |
Jonathan Gilley |
title |
Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
title_short |
Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
title_full |
Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
title_fullStr |
Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
title_full_unstemmed |
Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. |
title_sort |
endogenous nmnat2 is an essential survival factor for maintenance of healthy axons. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doaj.org/article/632fc2e9aedc4d568fd9d42964dccb81 |
work_keys_str_mv |
AT jonathangilley endogenousnmnat2isanessentialsurvivalfactorformaintenanceofhealthyaxons AT michaelpcoleman endogenousnmnat2isanessentialsurvivalfactorformaintenanceofhealthyaxons |
_version_ |
1718414580926906368 |