Drosophila melanogaster Models of Friedreich’s Ataxia
Table 2
Frataxin overexpression in Drosophila. The fh construct and the GAL4 driver used to obtain the different phenotypes are indicated.
Overexpression line
GAL4 driver line
Phenotypes
UAS-dfh1 and UAS-dfh2 [89]: fourfold increase in fh mRNA expression (25°C)
Actin Ubiquitous
(i) Viable adults [89] (ii) Increased lifespan [89] (iii) Significant increase in tolerance to iron-induced stress (FeCl3), paraquat, and H2O2 (measuring survival) [89] (iv) Significant increase in total antioxidant activity (bathocuproine dye) [89]
UAS-fh [34]: 9-fold increase in fh mRNA expression and a strong increase in protein levels (29°C)
Actin and Ubiquitous
(i) Lethal at early pupae or 3rd instar larvae at 29°C [34] (ii) Defects in developing muscles, axonal tracks, and axonal pathfinding (1D4 staining) and an increase in the number of sensory ventral neurons. No abnormalities detected in the CNS [34] (iii) At 25°C, viable adults that are sensitive to oxidative stress and iron [34, 96]. Young individuals have higher catalase and aconitase activities and ATP production than controls but are hypersensitive to hyperoxia [96]
Appl and elav Pan-neural
(i) Viable at 29°C and 25°C (ii) Reduced lifespan and climbing capability [95, 96]. Locomotor defects are rescued by mitochondrial catalase expression and mfrn silencing [96]. (iii) Reduced ferritin and mitoferrin levels [96] (iv) Brain vacuolization [96]
Other neuronal drivers neur Sensory organs and their precursors D42 Motor neurons Ddc Aminergic neurons TH Dopaminergic neurons c698a Brain
(i) Viable adults at 29°C and 25°C [34] (ii) Reduced climbing capability and lifespan at both temperatures (neur/D42) [34, 95]. (iii) Lifespan is recovered by mitochondrial catalase (neur) [95] (iv) Ddc, TH, and c698a: lifespan and climbing capability unaffected at 29°C or 25°C [34, 96] (v) Strong promotion of mitochondrial fusion and ROS-mediated cell death of dopaminergic neurons (TH) [96]
Repo Pan-glial
(i) Reduced lifespan and climbing capability [95] (ii) Expression of mitochondrial catalase increases lifespan and climbing capability [95]
Other tissues: Dot, heart and 24B, mesoderm
(i) Lethal from the early pupa stage to adult eclosion from the puparium at 29°C and 25°C [34, 95] (ii) Lack of some pericardial cells along the tubular structure of the developing heart (ECII staining) in embryos at 29°C [34]
UAS- [95]: Expression of human frataxin. Stronger phenotypes than UAS-fh (25°C)
Actin and Ubiquitous
(i) Lethal in pupae [95] (ii) Reduced aconitase activity in larvae [95] (iii) Reduced NDUFS3 protein levels in larvae [95]
(i) Reduced lifespan and climbing capability and increased sensitivity to oxidative insult [95] (ii) Expression of mitochondrial catalase increases lifespan [95]
Repo Pan-glial
(i) Morphological disruption of glial cells and formation of lipid droplets [95] (ii) Expression of mitochondrial catalase increases lifespan and improves climbing capability [95]
most used temperature in the experiments. -FXN triggers the same defects as UAS-fh. To avoid repetition, only new phenotypes have been included; CNS: Central Nervous System.
