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Autophagy balances a Highwire act in synapse development

NMJs are smaller in flies lacking Atg1 (left) and overgrown in flies overexpressing the protein (right).

Autophagy plays a surprisingly constructive role in Drosophila synapse development, counteracting a proteasome-mediated degradation pathway, say Shen and Ganetzky.

The E3 ubiquitin ligase Highwire (Hiw) limits neuromuscular junction (NMJ) growth presumably by sending proteins to their destruction at the hands of the proteasome. Shen and Ganetzky wondered whether protein degradation by autophagosomes might similarly regulate NMJ development.

Flies with impaired autophagy had smaller NMJs than wild-type flies, whereas overexpressing an inducer of autophagy called Atg1 caused NMJ overgrowth. Activating autophagy by feeding larvae with rapamycin also enlarged NMJs, indicating that the degradative pathway promotes rather than inhibits synaptic development. The supersized NMJs of flies overexpressing Atg1 were remarkably similar to those of hiw mutants, leading the authors to investigate whether the two pathways were linked. Hiw protein levels were reduced upon autophagy induction, while boosting levels of the ubiquitin ligase reversed the NMJ overgrowth induced by Atg1. Autophagy therefore promotes synaptogenesis by degrading Hiw and blocking its inhibitory effects.

Although it is usually thought of as a nonspecific catchall for protein destruction, there are a few examples where autophagy is more discriminating in its function. The authors therefore want to determine whether Hiw is specifically targeted for destruction by autophagosomes and, if so, how the process occurs. They point out that autophagy is ideally suited to regulating synaptic growth and remodeling because the pathway responds to a wide range of environmental cues.

References

Shen, W., B. Ganetzky, et al. 2009. J. Cell Biol. doi:10.1083/jcb.200907109.[Abstract/Free Full Text]

bshort{at}rockefeller.edu

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This Article Full Text (PDF, 487K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Short, B. PubMed Articles by Short, B. Social Bookmarking                            What's this?