ABSTRACT
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, the mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Drosophila melanogaster/metabolism , Mitochondrial Dynamics , Amyotrophic Lateral Sclerosis/genetics , Animals , Disease Models, Animal , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Gene Expression Regulation , Head , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mitochondrial Dynamics/genetics , Models, Biological , Protein Stability , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Glutathione transferase omega (GSTO) belongs to a recently identified family of glutathione transferase (GST) and presents several known functions. In Drosophila, despite the high sequence identity among the four GstO isoforms, they present different physiological functions. Herein, we showed that GstO1, which is one of the Drosophila GstOs, is highly expressed in adult heads. We determined the three-dimensional structure of GstO1, by homology modeling. Furthermore, we show that GstO1 loss-of-function mutant flies display reduced survival than the control flies when subjected to H2O2 treatment. Interestingly, the neuronal-specific expression of GstO1 in a GstO1 loss-of-function mutant background rescued H2O2-induced toxicity. We further showed that GstO1 inhibits H2O2-mediated activation of the mitogen-activated protein kinase (MAPK) pathway. Collectively, our findings provide valuable new insights into the tissue-specific protective mechanisms of Drosophila GstOs during oxidative stress.