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Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 i... more Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mito-chondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.
Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The p... more Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochon-drial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD.
Drafts by Andres Mesa
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / g e n t o x C o m m... more j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / g e n t o x C o m m u n i t y a d d r e s s : w w w. e l s e v i e r. c o m / l o c a t e / m u t r e s a b s t r a c t Flavonoids are a family of antioxidants that are widely represented in fruits, vegetables, dry legumes, and chocolate, as well as in popular beverages, such as red wine, coffee, and tea. The flavonoids chloro-genic acid, kaempferol, quercetin and quercetin 3-d-glycoside were investigated for genotoxicity using the wing somatic mutation and recombination test (SMART). This test makes use of two recessive wing cell markers: multiple wing hairs (mwh) and flare (flr 3), which are mutations located on the left arm of chromosome 3 of Drosophila melanogaster and are indicative of both mitotic recombination and various types of mutational events. In order to test the antioxidant capacities of the flavonoids, experiments were conducted with various combinations of oxidants and polyphenols. Oxidative stress was induced using hydrogen peroxide, the Fenton reaction and paraquat. Third-instar transheterozygous larvae were chronically treated for all experiments. The data obtained in this study showed that, at the concentrations tested, the flavonoids did not induce somatic mutations or recombination in D. melanogaster with the exception of quercetin, which proved to be genotoxic at only one concentration. The oxidants hydrogen peroxide and the Fenton reaction did not induce mutations in the wing somatic assay of D. melanogaster, while paraquat and combinations of flavonoids produced significant numbers of small single spots. Quercetin 3-d-glycoside mixed with paraquat was shown to be desmutagenic. Combinations of the oxidants with the other flavonoids did not show any antioxidant activity.
Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 i... more Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mito-chondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.
Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The p... more Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochon-drial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD.
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / g e n t o x C o m m... more j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / g e n t o x C o m m u n i t y a d d r e s s : w w w. e l s e v i e r. c o m / l o c a t e / m u t r e s a b s t r a c t Flavonoids are a family of antioxidants that are widely represented in fruits, vegetables, dry legumes, and chocolate, as well as in popular beverages, such as red wine, coffee, and tea. The flavonoids chloro-genic acid, kaempferol, quercetin and quercetin 3-d-glycoside were investigated for genotoxicity using the wing somatic mutation and recombination test (SMART). This test makes use of two recessive wing cell markers: multiple wing hairs (mwh) and flare (flr 3), which are mutations located on the left arm of chromosome 3 of Drosophila melanogaster and are indicative of both mitotic recombination and various types of mutational events. In order to test the antioxidant capacities of the flavonoids, experiments were conducted with various combinations of oxidants and polyphenols. Oxidative stress was induced using hydrogen peroxide, the Fenton reaction and paraquat. Third-instar transheterozygous larvae were chronically treated for all experiments. The data obtained in this study showed that, at the concentrations tested, the flavonoids did not induce somatic mutations or recombination in D. melanogaster with the exception of quercetin, which proved to be genotoxic at only one concentration. The oxidants hydrogen peroxide and the Fenton reaction did not induce mutations in the wing somatic assay of D. melanogaster, while paraquat and combinations of flavonoids produced significant numbers of small single spots. Quercetin 3-d-glycoside mixed with paraquat was shown to be desmutagenic. Combinations of the oxidants with the other flavonoids did not show any antioxidant activity.