Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis.
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.
Soochunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan 31151, South Korea.
Volodya
V
Altanbyek
Soochunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan 31151, South Korea.
Sun-Joo
SJ
Cha
Department of Medical Biotechnology, Soonchunhyang University, Asan 31538, South Korea.
Ga-Un
GU
Kang
Department of Chemistry, Soonchunhyang University, Asan 31538, South Korea.
Dai Sig
DS
Im
Korea Basic Research Institute Gwangju Center, Gwangju 61186, South Korea.
Seongsoo
S
Lee
Department of Convergence Brain Research, Korea Brain Research Institute, Daegu 41068, South Korea.
Hyung-Jun
HJ
Kim
Department of Medical Biotechnology, Soonchunhyang University, Asan 31538, South Korea. Electronic address: kiyoung2@sch.ac.kr.
Kiyoung
K
Kim
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006257:Head; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics; D008954:Models, Biological; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D044767:Ubiquitin-Protein Ligases; C487430:park protein, Drosophila
Amyotrophic lateral sclerosis; DNA/RNA-Binding protein; Drosophila; Mitochondrial dynamics; Mitochondrial dynamics regulatory proteins