Discordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity

Ann Neurol. 2021 Jan;89(1):158-164. doi: 10.1002/ana.25942. Epub 2020 Nov 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • DNA, Mitochondrial / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Phenotype
  • Twins, Monozygotic / genetics*


  • DNA, Mitochondrial