Hedgehog Signaling Modulates Glial Proteostasis and Lifespan

Abstract

Summary: 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. : Glial dysfunctions affect organismal lifespan and neuron integrity. Rallis et al. show that Hedgehog signaling coordinates lifespan determination and neuroprotection through the regulation of glial proteostasis during adult life in Drosophila. This process is mediated by the regulation of chaperones upon activation of Hedgehog signaling in glia. Keywords: Hedgehog, longevity, dopaminergic neurons, mobility, glial cell, proteostasis, cubitus interruptus, smoothened, heat shock proteins, Hsp40, Hsp68, ER stress