TY - JOUR
T1 - Discordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity
AU - Dulovic-Mahlow, Marija
AU - König, Inke R.
AU - Trinh, Joanne
AU - Diaw, Sokhna Haissatou
AU - Urban, Peter P.
AU - Knappe, Evelyn
AU - Kuhnke, Neele
AU - Ingwersen, Lena Christin
AU - Hinrichs, Frauke
AU - Weber, Joachim
AU - Kupnicka, Patrycja
AU - Balck, Alexander
AU - Delcambre, Sylvie
AU - Vollbrandt, Tillman
AU - Grünewald, Anne
AU - Klein, Christine
AU - Seibler, Philip
AU - Lohmann, Katja
N1 - Publisher Copyright:
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096699577&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/0280473c-0f03-3c5f-9c94-8d6f0cc79595/
U2 - 10.1002/ana.25942
DO - 10.1002/ana.25942
M3 - Journal articles
C2 - 33094862
AN - SCOPUS:85096699577
SN - 0364-5134
VL - 89
SP - 158
EP - 164
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -