A Role for the Molecular Chaperone Protein BiP/GRP78 in Drosophila Sleep Homeostasis

Study Objectives: Microarray studies have identified numerous genes that change in response to prolonged wakefulness. The challenge is to determine which transcriptional changes translate into protein changes that are critical for recovery following sleep loss. BiP is a protein indicator of endoplasmic reticulum (ER) stress, and BiP mRNA increases in mouse and rat cerebral cortex and in Drosophila heads in response to sleep loss. We first sought to determine whether the expression of BiP protein parallels sleep homeostatic drive and dissipates with recovery sleep. We then sought to establish a key role for BiP in the homeostatic process of sleep by contrasting recovery sleep in models of over- and under-expression of BiP. Subjects and Interventions: Drosophila melanogaster were used to take advantage of the UAS-Gal4 system to both over express wild-type BiP and express a dominant negative form of BiP. Results: BiP protein rises two and a half fold across sleep loss and falls in recovery sleep, in parallel with gene changes. BiP over expression in the flies leads to an increase in recovery sleep in response to sleep loss, in parallel with a delay in the unfolded protein response. Flies with the dominant negative mutation and reduced functional BiP show the opposite effect. Conclusions: We show directly that BiP protein, a key indicator of ER stress is instrumental in determining the amount of recovery sleep following enforced wakefulness. We have thus identified a novel window into regulation of sleep homeostasis.