Abstract
Author SummaryAxons degenerate after injury and during neurodegenerative diseases, but we are still searching for the cellular mechanism responsible for this degeneration. Here, using a nerve crush injury assay in the fruit fly Drosophila, we have identified a role for a conserved molecule named Highwire (Hiw) in the initiation of axonal degeneration. Hiw is an E3 ubiquitin ligase thought to regulate the levels of specific downstream proteins by targeting their destruction. We show that Hiw promotes axonal degeneration by regulating two independent downstream targets: the Wallenda (Wnd) kinase, and the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat). Interestingly, Nmnat has previously been implicated in a protective role in neurons. Our findings indicate that Nmnat protein is down-regulated in axons by Hiw and that this regulation plays a critical role in the degeneration of axons and synapses. The other target, the Wnd kinase, was previously known for its role in promoting new axonal growth after injury. We propose that Hiw coordinates multiple responses to regenerate damaged neuronal circuits after injury: degeneration of the distal axon via Nmnat, and new growth of the proximal axon via Wnd.
Highlights
Axon degeneration can be induced by a variety of insults, including injury
We show that Hiw promotes axonal degeneration by regulating two independent downstream targets: the Wallenda (Wnd) kinase, and the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat)
An attractive hypothesis is that Hiw promotes ubiquitination and protein turnover of endogenous Nmnat protein. Consistent with this hypothesis, we found that knockdown of nmnat suppressed the protection from degeneration caused by overexpression of the de-ubiquitinating enzyme UBP2 (Figure S3)
Summary
When an axon is transected from the cell body, the distal axon ‘‘stump’’ degenerates through a regulated selfdestruction process called Wallerian degeneration [1]. Previous studies have implicated a role for the ubiquitin proteasome system (UPS) in Wallerian degeneration, since inhibition of UPS leads to a delay in the early stages of degeneration [2,3]. One explanation for this result is that the UPS mediates bulk protein degradation via the combined action of many ubiquitin ligases. Using an in vivo assay for Wallerian degeneration in Drosophila, we identify an essential role for a specific E3 ubiquitin ligase in promoting Wallerian degeneration
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