Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration
College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, Korea.Human Molecular Genetics (Impact Factor: 6.39). 01/2013; 22(8). DOI: 10.1093/hmg/ddt006
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 the 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.
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ABSTRACT: Parkinson's disease (PD) is the most prevalent neurodegenerative movement disorder. Genetic studies over the past two decades have greatly advanced our understanding of the etiological basis of PD and elucidated pathways leading to neuronal degeneration. Recent studies have suggested that abnormal autophagy, a well conserved homeostatic process for protein and organelle turnover, may contribute to neurodegeneration in PD. Moreover, many of the proteins related to both autosomal dominant and autosomal recessive PD, such as α-synuclein, PINK1, Parkin, LRRK2, DJ-1, GBA, and ATPA13A2, are also involved in the regulation of autophagy. We propose that reduced autophagy enhances the accumulation of α-synuclein, other pathogenic proteins, and dysfunctional mitochondria in PD, leading to oxidative stress and neuronal death.Molecular Neurobiology 07/2014; 51(1). DOI:10.1007/s12035-014-8787-5 · 5.14 Impact Factor
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ABSTRACT: SUMO modification modulates the expression of defense genes in Drosophila, activated by the Toll/NF-κB and IMD/NF-κB signaling networks. We however have limited understanding of the SUMO modulated regulation of the immune response and lack information on SUMO targets in the immune system. In this study we have measured the changes to the SUMO proteome in S2 cells in response to an LPS challenge, identifying 1619 unique proteins in SUMO enriched lysates. A confident set of 710 proteins represents the immune induced SUMO proteome and analysis suggests that specific protein domains, cellular pathways and protein complexes respond to immune stress. A small subset of the confident set were validated by in-bacto SUMOylation and shown to be bona-fide SUMO targets. These include components of immune signaling pathways such as Caspar, Jra, Kay, cdc42, p38b, 14-3-3ε, as also cellular proteins with diverse functions, many being components of protein complexes, such as prosβ4, Rps10b, SmD3, Tango7 and Aats-arg. Caspar, a human FAF1 ortholog that negatively regulates IMD signaling, is SUMOylated at K551, and responds to LPS treatment in cultured cells. Our study is one of the first to describe SUMO proteome for the Drosophila immune response. Our data and analysis provide a global framework for the understanding of SUMO modification in the host response to pathogens.G3-Genes Genomes Genetics 08/2015; DOI:10.1534/g3.115.020958 · 3.20 Impact Factor
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