Discordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity.
Ann Neurol
; 89(1): 158-164, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-33094862
ABSTRACT
OBJECTIVE:
Even though genetic predisposition has proven to be an important element in Parkinson's disease (PD) etiology, monozygotic (MZ) twins with PD displayed a concordance rate of only about 20% despite their shared identical genetic background.METHODS:
We recruited 5 pairs of MZ twins discordant for idiopathic PD and established skin fibroblast cultures to investigate mitochondrial phenotypes in these cellular models against the background of a presumably identical genome. To test for genetic differences, we performed whole genome sequencing, deep mitochondrial DNA (mtDNA) sequencing, and tested for mitochondrial deletions by multiplex real-time polymerase chain reaction (PCR) in the fibroblast cultures. Further, the fibroblast cultures were tested for mitochondrial integrity by immunocytochemistry, immunoblotting, flow cytometry, and real-time PCR to quantify gene expression.RESULTS:
Genome sequencing did not identify any genetic difference. We found decreased mitochondrial functionality with reduced cellular adenosine triphosphate (ATP) levels, altered mitochondrial morphology, elevated protein levels of superoxide dismutase 2 (SOD2), and increased levels of peroxisome proliferator-activated receptor-gamma coactivator-α (PPARGC1A) messenger RNA (mRNA) in skin fibroblast cultures from the affected compared to the unaffected twins. Further, there was a tendency for a higher number of somatic mtDNA variants among the affected twins.INTERPRETATION:
We demonstrate disease-related differences in mitochondrial integrity in the genetically identical twins. Of note, the clinical expression matches functional alterations of the mitochondria. ANN NEUROL 2021;89158-164.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Gêmeos Monozigóticos
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DNA Mitocondrial
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Predisposição Genética para Doença
/
Mitocôndrias
Limite:
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article