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Discordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity
Author(s) -
DulovicMahlow Marija,
König Inke R.,
Trinh Joanne,
Diaw Sokhna Haissatou,
Urban Peter P.,
Knappe Evelyn,
Kuhnke Neele,
Ingwersen LenaChristin,
Hinrichs Frauke,
Weber Joachim,
Kupnicka Patrycja,
Balck Alexander,
Delcambre Sylvie,
Vollbrandt Tillman,
Grünewald Anne,
Klein Christine,
Seibler Philip,
Lohmann Katja
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25942
Subject(s) - biology , mitochondrial dna , sod2 , genetics , mitochondrion , human mitochondrial genetics , tfam , mitochondrial disease , ppargc1a , monozygotic twin , microbiology and biotechnology , gene , endocrinology , superoxide dismutase , coactivator , oxidative stress , transcription factor
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;89:158–164