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Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration.

ABSTRACT: Injured axons undergo a controlled, self-destruction process, known as Wallerian degeneration. However, the underlying mechanism remains elusive. Using the Drosophila wing nerve as a model, we identify the ESCRT component Vps4 as a previously unidentified essential gene for axonal integrity. Up-regulation of Vps4 remarkably delays degeneration of injured axons. We further reveal that Vps4 is required and sufficient to promote autophagic flux in axons and mammalian cells. Moreover, using both in vitro and in vivo models, we show that the function of Vps4 in maintaining axonal autophagy and suppressing Wallerian degeneration is conserved in mammals. Last, we uncover that Vps4 protein is rapidly depleted in injured mouse axons, which may underlie the injury-induced autophagic impediment and the subsequent axonal degeneration. Together, Vps4 and ESCRT may represent a novel signal transduction mechanism in axon injury and Wallerian degeneration.

SUBMITTER: Wang H

PROVIDER: S-EPMC6374107 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration.

Wang Haiqiong H Wang Xuejie X Zhang Kai K Wang Qingyao Q Cao Xu X Wang Zhao Z Zhang Shuang S Li Ang A Liu Kai K Fang Yanshan Y

Science advances 20190213 2

Injured axons undergo a controlled, self-destruction process, known as Wallerian degeneration. However, the underlying mechanism remains elusive. Using the Drosophila wing nerve as a model, we identify the ESCRT component Vps4 as a previously unidentified essential gene for axonal integrity. Up-regulation of Vps4 remarkably delays degeneration of injured axons. We further reveal that Vps4 is required and sufficient to promote autophagic flux in axons and mammalian cel ...[more]

PMID: 30788439

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Project description:BackgroundThe progressive nature of Wallerian degeneration has long been controversial. Conflicting reports that distal stumps of injured axons degenerate anterogradely, retrogradely, or simultaneously are based on statistical observations at discontinuous locations within the nerve, without observing any single axon at two distant points. As axon degeneration is asynchronous, there are clear advantages to longitudinal studies of individual degenerating axons. We recently validated the study of Wallerian degeneration using yellow fluorescent protein (YFP) in a small, representative population of axons, which greatly improves longitudinal imaging. Here, we apply this method to study the progressive nature of Wallerian degeneration in both wild-type and slow Wallerian degeneration (WldS) mutant mice.ResultsIn wild-type nerves, we directly observed partially fragmented axons (average 5.3%) among a majority of fully intact or degenerated axons 37-42 h after transection and 40-44 h after crush injury. Axons exist in this state only transiently, probably for less than one hour. Surprisingly, axons degenerated anterogradely after transection but retrogradely after a crush, but in both cases a sharp boundary separated intact and fragmented regions of individual axons, indicating that Wallerian degeneration progresses as a wave sequentially affecting adjacent regions of the axon. In contrast, most or all WldS axons were partially fragmented 15-25 days after nerve lesion, WldS axons degenerated anterogradely independent of lesion type, and signs of degeneration increased gradually along the nerve instead of abruptly. Furthermore, the first signs of degeneration were short constrictions, not complete breaks.ConclusionsWe conclude that Wallerian degeneration progresses rapidly along individual wild-type axons after a heterogeneous latent phase. The speed of progression and its ability to travel in either direction challenges earlier models in which clearance of trophic or regulatory factors by axonal transport triggers degeneration. WldS axons, once they finally degenerate, do so by a fundamentally different mechanism, indicated by differences in the rate, direction and abruptness of progression, and by different early morphological signs of degeneration. These observations suggest that WldS axons undergo a slow anterograde decay as axonal components are gradually depleted, and do not simply follow the degeneration pathway of wild-type axons at a slower rate.

Dataset Information

Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration.

Publications

Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration.

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