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1.
Biochim Biophys Acta ; 1862(4): 754-762, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26804652

RESUMO

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905+1G>A) and the combined presence of three risk variants in DPYD (c.1905+1G>A, c.1129-5923C>G, c.2846A>T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846A>T mutation and a novel nonsense mutation c.1681C>T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.


Assuntos
Códon sem Sentido , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Haplótipos , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Substituição de Aminoácidos , Deficiência da Di-Hidropirimidina Desidrogenase/sangue , Feminino , Células HEK293 , Humanos , Pessoa de Meia-Idade , Uracila/sangue
2.
Neurobiol Aging ; 35(7): 1596-604, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24524963

RESUMO

BRI2 protein binds amyloid precursor protein to halt amyloid-ß production and inhibits amyloid-ß aggregation via its BRICHOS-domain suggesting a link between BRI2 and Alzheimer's disease (AD). Here, we investigate the possible involvement of BRI2 in human AD pathogenesis. BRI2 containing BRICHOS-domain was increased up to 3-fold in AD hippocampus (p = 0.003, n = 14/group). Immunohistochemistry showed BRI2 deposits associated with amyloid-ß plaques in early pathologic stages (Braak-III; Thal-2/3). We observed a decrease in the protein levels of ADAM10 (p = 0.02) and furin (p = 0.066), as well as an increase in SPPL2b (p < 0.0001) in AD hippocampus. Because these enzymes are involved in BRI2 processing, their changes may lead to aberrant processing of BRI2 promoting its deposition and likely affecting BRI2 function. Loss of BRI2 function in AD was supported by the decreased presence of BRI2-amyloid precursor protein complexes in the hippocampus of AD patients compared with control subjects. In conclusion, our data obtained from human samples indicate that in early stages of AD there is an increased deposition of BRI2, which likely leads to impaired BRI2 function thereby influencing AD pathophysiology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Glicoproteínas de Membrana/fisiologia , Placa Amiloide/genética , Proteínas Adaptadoras de Transdução de Sinal , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/metabolismo , Complexos Multiproteicos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ligação Proteica , Estrutura Terciária de Proteína
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