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Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects.
Soltys, Daniela T; Pereira, Carolina P M; Rowies, Fernanda T; Farfel, José M; Grinberg, Lea T; Suemoto, Claudia K; Leite, Renata E P; Rodriguez, Roberta D; Ericson, Nolan G; Bielas, Jason H; Souza-Pinto, Nadja C.
Afiliação
  • Soltys DT; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
  • Pereira CPM; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
  • Rowies FT; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
  • Farfel JM; Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
  • Grinberg LT; Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil; Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
  • Suemoto CK; Division of Geriatrics, University of São Paulo Medical School, São Paulo, SP, Brazil.
  • Leite REP; Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
  • Rodriguez RD; Department of Neurology, Behavioral and Cognitive Neurology Unit, University of São Paulo, São Paulo, SP, Brazil.
  • Ericson NG; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Bielas JH; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Souza-Pinto NC; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil. Electronic address: nadja@iq.usp.br.
Neurobiol Aging ; 73: 161-170, 2019 01.
Article em En | MEDLINE | ID: mdl-30359878
Accumulation of oxidative mitochondrial DNA (mtDNA) damage and impaired base excision repair (BER) in brains have been associated with Alzheimer's disease (AD). However, it is still not clear how these affect mtDNA stability, as reported levels of mtDNA mutations in AD are conflicting. Thus, we investigated whether alterations in BER correlate with mtDNA instability in AD using postmortem brain samples from cognitively normal AD subjects and individuals who show neuropathological features of AD, but remained cognitively normal (high-pathology control). To date, no data on DNA repair and mtDNA stability are available for these individuals. BER activities, mtDNA mutations, and mtDNA copy number were measured in the nuclear and mitochondrial extracts. Significantly lower uracil DNA glycosylase activity was detected in nuclear and mitochondrial extracts from AD subjects, while apurinic/apyrimidinic endonuclease activity was similar in all groups. Although mtDNA mutation frequency was similar in all groups, mtDNA copy number was significantly decreased in the temporal cortex of AD brains but not of high-pathology control subjects. Our results show that lower mitochondrial uracil DNA glycosylase activity does not result in increased mutagenesis, but rather in depletion of mtDNA in early-affected brain regions during AD development.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / DNA Mitocondrial / Reparo do DNA / Doença de Alzheimer Tipo de estudo: Risk_factors_studies Limite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Neurobiol Aging Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / DNA Mitocondrial / Reparo do DNA / Doença de Alzheimer Tipo de estudo: Risk_factors_studies Limite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Neurobiol Aging Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos