A Drosophila Wolfram Syndrome 1 (WFS1) homologue synergises with the intracellular Ca²⁺ release channel, IP₃R to affect mitochondrial morphology and function

Abstract

Wolfram 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 IP₃ mediated Ca²⁺ release from the endoplasmic 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 of Drosophila melanogaster. We show strong genetic interactions between trans-heterozygotes of wfs1 and itpr (IP₃R) mutants by measuring flight deficits. Over-expression of wild-type cDNAs of either interacting partner, wfs1⁺ or itpr⁺ 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. In wfs1 mutant as well as wfs1 knockdown 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 of Drosophila, for optimal mitochondrial Ca²⁺ entry and maintaining mitochondrial morphology. Our study demonstrates that Drosophila can 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.