Drosophila REEP1 modulates ER morphology and ER stress

Defects in endoplasmic reticulum (ER) membrane shaping and in lipid metabolism seem to be crucial mechanisms underlying Hereditary Spastic Paraplegia (HSP), a complex genetic disorder characterized by the axonal degeneration of corticospinal tracts. Here we report the analysis of a Drosophila melanogaster model of SPG31, an autosomal dominant form of HSP caused by mutations in the Receptor Expression Enhancing Protein1 gene (REEP1). REEP1 coordinates ER shaping within the tubular ER and confers resistance to ER stress in neurons, but the mechanism of this effect remains to be elucidated. In this work, we analyzed the effects of loss of D-REEP1 (REEPA) on the ER morphology, the Unfolded Protein Response (UPR), the locomotor activity and longevity. The absence of REEPA negatively affected longevity reducing lifespan as well as the locomotor activity. Moreover, REEPA mutant presented a larger proportion of apparent ER sheets, the up-regulation of ER-stress sensor Bip, the activation of Ire1 and ATF6 pathways, and a drastic reduction of the transcription level of two major enzymes involved in LDs biogenesis. The administration to REEPA mutant of naringenin, a flavanone known for its neuroprotective effects, rescued lifespan defect and ER homeostasis by decreasing UPR activation and enhancing LDs biogenesis, thus representing a promising strategy for the management of HSP symptoms.