Objective: To identify genetic modifiers related to G-protein coupled receptor signaling pathways, which might improve a frataxin-depleted phenotype in a Drosophila model of Friedreich’s ataxia.

Background: Friedreich’s ataxia (FRDA) is a neurodegenerative and hereditary disease, affecting both the central and peripheral nervous systems and the heart. It is caused by the deficiency of the frataxin protein, involved in the biosynthesis of the iron-sulfur clusters in the mitochondria.  It is proposed that alterations in G-protein coupled receptor signaling pathways are involved in the pathophysiological mechanism of the disease.  Our working hypothesis is that modifying the expression of genes that act in these signaling pathways could improve the phenotypes associated with frataxin deficiency.  This study would contribute to find a therapeutic target in FRDA, a disease that currently lack an effective treatment.

Method: We used a D. melanogaster model of FRDA, previously obtained in our laboratory (1). Model flies show a reduction in their climbing capacity of 25% compared to control flies. To identify genetic modifiers of the motor impairment of the FRDA model flies, we conducted a genetic screen of G-protein coupled receptor signaling pathways. Specifically, we examined the effect of 133 knockdown alleles (GPCR alleles) on this phenotype. The transgenic RNAi lines were obtained from the Vienna Drosophila Resource Center. The climbing assays were performed as indicated in Calap-Quintana et al (2).

Results: We found that 13 GPCR alleles altered the climbing phenotype, 33 produced lethality and 87 did not change the motor dysfunction of the FRDA model flies.  The knockdown of the genes 5-HT2A, Pk1r, AkhR, Ir56d, CCAP-R and CCHa2-R suppressed the frataxin-depleted phenotype. In all cases, the effect of the corresponding alleles on their own had no effect on the viability or motor performance of control flies.

Conclusion: We have found 5 genes related to G-protein coupled receptor signaling pathway that improved the climbing ability of the FRDA model flies. Most of them encode receptors coupled to the Gq subunit, being able to act on calcium homeostasis and its signaling.  The improvement of motor performance in the model flies might due to reduction of cytosolic Ca+2 overload that has been observed in other models of the disease.

References: (1) Llorens JV, Navarro J a, Martínez-Sebastián MJ, Baylies MK, Schneuwly S, Botella J a, et al. Causative role of oxidative stress in a Drosophila model of Friedreich ataxia. FASEB J. 2007, 21(2):333–344. DOI: 10.1096/fj.05-5709com (2) TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia Pablo Calap-Quintana1, Sirena Soriano1,2, José Vicente Llorens1¤, Ismael Al-Ramahi2,Juan Botas2, María Dolores Moltó1,3*, María José Martínez-Sebastián1. PLoS ONE, 10 (2015), p. e0132376 doi: 10.1371/journal.pone.0132376

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-modifier-genes-related-to-g-proteins-pathways-on-the-motor-capacity-of-a-drosophila-melanogaster-model-of-friedreichs-ataxia/