Hedgehog Signalling Modulates Glial Proteostasis and Lifespan

Abstract

SUMMARYThe conserved Hedgehog (Hh) signaling pathway has a well-established role in animal development, however its function during adulthood remains largely unknown. Here, we investigated whether the Hh signaling pathway is active during adult life in Drosophila melanogaster and uncovered a protective function for Hh signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hh reduces lifespan, locomotor activity and dopaminergic neuron integrity. Conversely, increased expression of Hh extends lifespan and improves fitness. Moreover, Hh pathway activation in glia rescues the lifespan and age-associated defects of hedgehog (hh) mutants. At the molecular level, the Hh pathway regulates downstream chaperones, principally hsp40 and hsp68, whose overexpression in glial cells rescues the shortened lifespan and proteostasis defects of hh mutants. Finally, we demonstrate the protective ability of Hh signalling in a Drosophila Alzheimer’s disease model expressing human Amyloid Beta (Aβ1-42) in the glia. Overall, we propose that Hh signalling is requisite for lifespan determination and correct proteostasis in glial cells and may have potential in ameliorating a wide range of degenerative diseases.