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
Source: PubMed


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.

  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Jul 2014 · Molecular Neurobiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative disorders, e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the progressive loss of neurons and subsequent cognitive decline. They are mainly found in older populations. Due to increasing life expectancies, the toll inflicted upon society by these disorders continues to become heavier and more prominent. Despite extensive research, however, the exact etiology of these disorders is still unknown, though the pathophysiological mechanisms have been attributed to oxidative, inflammatory and apoptotic injury in the brain. Moreover, there is currently no promising therapeutic agent against these neurodegenerative changes. Catalpol, an iridoid glucoside contained richly in the roots of the small flowering plant species Rehmannia glutinosa Libosch, has been shown to have antioxidation, anti-inflammation, anti-apoptosis and other neuroprotective properties and plays a role in neuroprotection against hypoxic/ischemic injury, AD and PD in both in vivo and in vitro models. It may therefore represent a potential therapeutical agent for the treatment of hypoxic/ischemic injury and neurodegenerative diseases. Based on our studies and those of others in the literature, here we comprehensively review the role of Catalpol in neuroprotection against pathological conditions, especially in neurodegenerative states and the potential mechanisms involved.
    No preview · Article · Jan 2015 · Current Medicinal Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.
    No preview · Article · Feb 2015 · Archive für Toxikologie
Show more