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

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 (Wld(S)) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (Nmnat1) portion of Wld(S) is required, we found that its nicotinamide adenine dinucleotide (NAD(+)) enzyme activity and the Wld(S) N-terminus (N70) are dispensable, unlike axotomy models of neurodegeneration. We suggest that Wld(S)-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.

Signal strength and signal duration define two distinct aspects of JNK-regulated axon stability.

Signaling proteins often control multiple aspects of cell morphogenesis. Yet the mechanisms that govern their pleiotropic behavior are often unclear. Here we show activity levels and timing mechanisms determine distinct aspects of Jun N-terminal kinase (JNK) pathway dependent axonal morphogenesis in Drosophila mushroom body (MB) neurons. In the complete absence of Drosophila JNK (Basket), MB axons fail to stabilize, leading to their subsequent degeneration. However, with a partial loss of Basket (Bsk), or of one of the upstream JNK kinases, Hemipterous or Mkk4, these axons overextend. This suggests that Bsk activity prevents axons from destabilizing, resulting in degeneration and overextension beyond their terminal targets. These distinct phenotypes require different threshold activities involving the convergent action of two distinct JNK kinases. We show that sustained Bsk signals are essential throughout development and act additively but are dispensable at adulthood. We also suggest that graded Bsk inputs are translated into AP-1 transcriptional outputs consisting of Fos and Jun proteins.

Hedgehog Signaling Modulates Glial Proteostasis and Lifespan.

The conserved Hedgehog signaling pathway has well-established roles in development. However, its function during adulthood remains largely unknown. Here, we investigated whether the Hedgehog signaling pathway is active during adult life in Drosophila melanogaster, and we uncovered a protective function for Hedgehog signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hedgehog reduces lifespan, locomotor activity, and dopaminergic neuron integrity. Conversely, increased expression of Hedgehog extends lifespan and improves fitness. Moreover, Hedgehog pathway activation in glia rescues the lifespan and age-associated defects of hedgehog mutants. The Hedgehog pathway regulates downstream chaperones, whose overexpression in glial cells was sufficient to rescue the shortened lifespan and proteostasis defects of hedgehog mutants. Finally, we demonstrate the protective ability of Hedgehog signaling in a Drosophila Alzheimer's disease model expressing human amyloid beta in the glia. Overall, we propose that Hedgehog signaling is requisite for lifespan determination and correct proteostasis in glial cells.