Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia

Abstract

Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.

Disarrangement of Endoplasmic reticulum-mitochondria communication impairs Ca2+homeostasis in FRDA

“…In order to test this hypothesis in an in vivo model, we decided to take advantage of the outstanding tools for genetic studies offered by the fruit fly (Drosophila melanogaster). Drosophila FRDA models have provided along the last decade several evidences about FRDAdependent mechanisms beyond the state of the art (Monnier et al, 2018). Our results with the overexpression of MCU are in favor of the hypothesis that increasing the Ca 2+ uptake by the mitochondria is neuroprotective in FRDA flies.…”

Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model

“…In this case, we used a second frataxin RNAi line because fh RNAi-2 is compatible with a normal development compared to the lethality induced by fh RNAi-1 (reviewed in Ref. [ 37 ]) when the silencing of frataxin is ubiquitous ( actin -G4). Unexpectedly, the strong ubiquitous overexpression of MCU achieved with the UAS- MCUoe lines led to some deleterious effects even in control flies.…”

“…To test this hypothesis in an in vivo model, we decided to take advantage of the outstanding tools for genetic studies offered by the fruit fly ( Drosophila melanogaster ). Drosophila FRDA models have provided along the last decade several evidences about FRDA-dependent mechanisms beyond the state of the art [ 37 ]. Our results with the overexpression of MCU are in favor of the hypothesis that increasing the Ca 2+ uptake by the mitochondria is neuroprotective in FRDA flies.…”

“…Genetic interactions were carried out by mating virgin females from the stocks fhRNAi-1 /CyO; Repo-GAL4 /TM6B tub -GAL80 or fhRNAi-2 /CyO; actin-GAL4 /TM6B tub -GAL80 with males of the corresponding UAS line. The ability of these two RNAi strains to silence frataxin expression in several tissues by means of the UAS-GAL4 system has been recently reviewed [ 37 ]. The stocks used in this work are described in Table S1 .…”

Drug screening in Drosophila; why, when, and when not?

“…The third neurological disorder to be modeled in Drosophila was Friedreich's Ataxia, a neurodegenerative disorder that results from mutations in the frataxin (FXN) gene (reviewed in Monnier, Llorens, & Navarro, 2018). Additional pathological features of FA include loss of vision and hearing and heart defects.…”