FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration.
Cumulative damage caused by oxidative stress results in diverse pathological conditions. Therefore, elucidating the molecular mechanisms underlying cell death following oxidative stress is important. Here, we describe a novel role for Fas-associated factor 1 (FAF1) as a crucial regulator of necrotic cell death elicited by hydrogen peroxide. Upon oxidative insult, FAF1 translocated from the cytoplasm to the nucleus and promoted the catalytic activation of poly(ADP-ribose) polymerase 1 (PARP1) through physical interaction. Moreover, FAF1 depletion prevented PARP1-linked downstream events involved in the triggering of cell death, including energetic collapse, mitochondrial depolarization and nuclear translocation of apoptosis-inducing factor (AIF), implying that FAF1 has a key role in PARP1-dependent necrosis in response to oxidative stress. We further investigated whether FAF1 might contribute to the pathogenesis of Parkinson's disease through excessive PARP1 activation. Indeed, the overexpression of FAF1 using a recombinant adeno-associated virus system in the mouse ventral midbrain promoted PARP1 activation and dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Collectively, our data demonstrate the presence of an FAF1-PARP1 axis that is involved in oxidative stress-induced necrosis and in the pathology of Parkinson's disease.
Department of Biological Sciences, Chungnam National University, Daejeon 305-764, Korea.
Changsun
C
Yu
Department of Biological Sciences, Chungnam National University, Daejeon 305-764, Korea.
Bok-Seok
BS
Kim
Department of Biological Sciences, Chungnam National University, Daejeon 305-764, Korea.|Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Korea.
Eunhee
E
Kim
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D055162:Biocatalysis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C490780:FAF1 protein, human; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C494830:AIFM1 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases
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