title: Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration.
abstract: This study reports the physical and functional interplay between Fas-associated factor 1 (FAF1), a death-promoting protein, and parkin, a key susceptibility protein for Parkinson's disease (PD). We found that parkin acts as an E3 ubiquitin ligase to ubiquitinate FAF1 both in vitro and at cellular level, identifying FAF1 as a direct substrate of parkin. The loss of parkin function due to PD-linked mutations was found to disrupt the ubiquitination and degradation of FAF1, resulting in elevated FAF1 expression in SH-SY5Y cells. Moreover, FAF1-mediated cell death was abolished by wild-type parkin, but not by PD-linked parkin mutants, implying that parkin antagonizes the death potential of FAF1. This led us to investigate whether FAF1 participates in the pathogenesis of PD. To address this, we used a gene trap mutagenesis approach to generate mutant mice with diminished levels of FAF1 (Faf1(gt/gt)). Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of PD, we found that FAF1 accumulated in the substantia nigra pars compacta (SNc) of MPTP-treated PD mice, and that MPTP-induced dopaminergic cell loss in the SNc was significantly attenuated in Faf1(gt/gt) mice versus Faf1(+/+) mice. MPTP-induced reduction of locomotor activity was also lessened in Faf1(gt/gt) mice versus Faf1(+/+) mice. Furthermore, we found that FAF1 deficiency blocked PD-linked biochemical events, including caspase activation, ROS generation, JNK activation and cell death. Taken together, these results suggest a new role for FAF1: that of a positive modulator for PD.
authors: College of Biological Sciences and Biotechnology, School of Medicine, Chungnam National University, Daejeon, South Korea.
authors: Jee-Won
authors: JW
authors: Sul
authors: Min-Young
authors: MY
authors: Park
authors: Juhee
authors: J
authors: Shin
authors: Young-Ran
authors: YR
authors: Kim
authors: Sung-Eun
authors: SE
authors: Yoo
authors: Young-Yun
authors: YY
authors: Kong
authors: Ki-Sun
authors: KS
authors: Kwon
authors: Young Ho
authors: YH
authors: Lee
authors: Eunhee
authors: E
authors: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein