AbstractWolfram syndrome (WFS) is an autosomal recessive neurodegenerative disorder, 90% of which is caused by loss of function of the endoplasmic reticular membrane protein Wolframin or WFS 1. Wolfram syndrome results in Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD) in humans. In mammalian cells WFS1 interacts with the ER-localised intracellular Ca2+release channel, Inositol Trisphosphate Receptor 1 (IP3R1) required for IP3mediated Ca2+release from the

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... reticulum.Here, we tested functional interactions between IP3R and WFS1 mutants in the context of organismal behaviour and neuronal mitochondrial morphology and physiology in a subset of central dopaminergic neurons ofDrosophila melanogaster. We show strong genetic interactions between trans-heterozygotes ofwfs1anditpr(IP3R) mutants by measuring flight deficits. Over-expression of wild-type cDNAs of either interacting partner,wfs1+oritpr+rescued the flight deficits. Cellular studies demonstrate changes in mitochondrial Ca2+entry accompanied by enlarged or swollen mitochondria and decreased mitochondrial content in genotypes that are flight defective. Inwfs1mutant as well aswfs1knockdown conditions a reduction in the number of dopaminergic neurons was observed.Thus, WFS1 interaction with the IP3R is required in flight regulating central dopaminergic neurons ofDrosophila, for optimal mitochondrial Ca2+entry and maintaining mitochondrial morphology. Our study demonstrates thatDrosophilacan be a good model system to understand the cellular and molecular basis of Wolfram syndrome, its impact on systemic physiology and suggests its use in testing putative pharmaceutical interventions.