상세 정보

underline
Metadata Downloads : dc(xml) or Excel
Cited 0 time in scopus ci

Title 

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

Authors 

J W SulM Y ParkJ ShinY R KimS E YooY Y KongKi Sun KwonY H LeeE Kim

Publisher 

Oxford University Press (OUP)

Issue Date 

2013

Citation 

Human Molecular Genetics, vol. 22, no. 8, pp. 1558-1573

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

Link 

http://dx.doi.org/10.1093/hmg/ddt006

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


There are no files associated with this item.
qrcode

FusionCharts.
DSpace Software Coptright(c) 2010 MIT and Hewleft-Packard  /  KRIBB-REPOSITORY ( Email:jakim@kribb.re.kr)