Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration

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Title
Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration
Author(s)
J W Sul; M Y Park; J Shin; Y R Kim; S E Yoo; Y Y Kong; Ki Sun Kwon; Y H Lee; E Kim
Bibliographic Citation
Human Molecular Genetics, vol. 22, no. 8, pp. 1558-1573
Publication Year
2013
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 (Faf1gt/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 Faf1gt/gt mice versus Faf1+/+ mice. MPTP-induced reduction of locomotor activity was also lessened in Faf1gt/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.
ISSN
0964-6906
Publisher
Oxford Univ Press
DOI
http://dx.doi.org/10.1093/hmg/ddt006
Type
Article
Appears in Collections:
Division of Research on National Challenges > Aging Research Center > 1. Journal Articles
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