The identification of Mendelian mutations in rare forms of familial Parkinson's disease (PD) have provided significant insights into the molecular pathogenesis of this common complex disorder. DJ-1 is the third of four genes known to be definitively causal in familial PD, the three others being alpha-synuclein, parkin and the recently identified PINK1. Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1-5 of the gene and an Italian kindred with a homozygous L166P missense mutation. The clinical phenotype of the two families was similar to that of parkin cases. Age of onset was in the mid-thirties with good responsiveness to l-dopa and slow disease progression. Focal dystonias and blepharospasm were also evident as were behavioural disturbances early in the course of the disease. To date, there are no studies of pathological material from known DJ-1 patients. It therefore remains to be determined whether these patients form Lewy bodies and/or Lewy neurites, the eosinophilic fibrillary inclusions that contain predominantly alpha-synuclein and that are the pathological hallmark of PD.
"It is ubiquitously expressed in a variety of mammalian tissues including the brain, and was initially described in association with oncogenesis and male rat infertility [1,4,5]. Later it was shown to be associated with autosomal recessive early-onset Parkinson's disease (PD) [3,6]. A few PD-causing mutations have been identified including exon deletions, truncations, homozygous and heterozygous point mutations, which predominantly result in loss of function [3,7]. "
[Show abstract][Hide abstract] ABSTRACT: DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD). Various mutations in the DJ-1 (PARK7) gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in DJ-1 and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient.
The possible effect of the deletion on promoter activity was investigated using a Dual-Luciferase Reporter assay. The DJ-1 5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2)-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (in silico) cis-regulatory analysis of DJ-1 promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH and rVISTA platforms.
A novel 16 bp deletion variant (g.-6_+10del) was identified in DJ-1 which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2)-M17 cells compared to the wild-type (P < 0.0001), indicating the importance of the 16 bp sequence in transcription regulation. The activity of both constructs was up-regulated during oxidative stress. Bioinformatic analysis revealed putative binding sites for three transcription factors AhR, ARNT, HIF-1 within the 16 bp sequence. The frequency of the g.-6_+10del variant was determined to be 0.7% in South African PD patients (2 heterozygotes in 148 individuals).
This is the first report of a functional DJ-1 promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the DJ-1 promoter and whether this variant confers a risk for PD.
BMC Medical Genetics 10/2009; 10:105. DOI:10.1186/1471-2350-10-105 · 2.08 Impact Factor
"Furthermore, we have successfully identified at least two proteins associated with oxidative stress related cytotoxicity: DJ-1 and cofilin. DJ-1 was identified as an oncogenic protein, related to Parkinson's disease and responsive to oxidative stress    . Several lines of evidence have shown that DJ-1 functions as an antioxidant protein. "
[Show abstract][Hide abstract] ABSTRACT: Trans, trans-2,4-decadienal (tt-DDE), a specific type of dienaldehyde, is abundant in heated oils or cooking oil fumes. Ingestion of heated oils and exposure to cooking oil fumes has been suggested to have a great health impact in a variety of organs, including the lungs. Previous studies have demonstrated that acute exposures to high doses of tt-DDE have induced oxidative stress, genotoxicity, and cytotoxicity in human lung cells. The objective in utilizing proteomic techniques of this study was to identify protein biomarkers associated with tt-DDE-induced oxidative stress and cytotoxicity in human bronchial epithelial cells BEAS-2B. Experimental results suggested that DJ-1 and cofilin proteins were protein biomarkers for tt-DDE-induced cytotoxicity and oxidative stress in lung cells. DJ-1 was especially an early biomarker for tt-DDE exposure.
Biochemical and Biophysical Research Communications 10/2008; 376(3):519-24. DOI:10.1016/j.bbrc.2008.09.020 · 2.30 Impact Factor
"Parkinson’s disease (PD) is a common movement disorder that affects individuals who are >60 years old (1–3). The disease is characterized by slowness of movement, resting tremor, rigidity and disturbances of gait and posture. "
[Show abstract][Hide abstract] ABSTRACT: The mechanism by which the Parkinson's disease-related protein alpha-synuclein (alpha-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from alpha-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing alpha-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes--ENT3, IDP3, JEM1, ARG2 and HSP82--ranked highest in their ability to block alpha-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of alpha-syn as judged by growth defects compared with wild-type cells expressing alpha-syn, which indicates that these genes protect cells from alpha-syn. Strikingly, four of the five genes are specific for alpha-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that alpha-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes alpha-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of alpha-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans.
Human Molecular Genetics 10/2008; 17(23):3784-95. DOI:10.1093/hmg/ddn276 · 6.39 Impact Factor
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