Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

Abstract

Axon degeneration is observed at the early stages of many neurodegenerative conditions and this often leads to subsequent neuronal loss. We previously showed that inactivating the c-Jun N-terminal kinase (JNK) pathway leads to axon degeneration in Drosophila mushroom body (MB) neurons. To understand this process, we screened candidate suppressor genes and found that the Wallerian degeneration slow (WldS) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (Nmnat1) portion of WldS is required, we found that its nicotinamide adenine dinucleotide (NAD+) enzyme activity and the WldS N-terminus (N70) are dispensable, unlike axotomy models of neurodegeneration. We suggest that WldS-Nmnat protects against axonal degeneration through chaperone activity. Furthermore, ectopically expressed heat shock proteins (Hsp26 and Hsp70) also protected against JNK and Nmnat degeneration phenotypes. These results suggest that molecular chaperones are key in JNK- and Nmnat-regulated axonal protective functions. © 2013. Published by The Company of Biologists Ltd.