Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family

Recent data suggesting complex I dysfunction in Parkinson's disease (PD) ar ises from mitochondrial DNA (mtDNA) mutation does not conclusively answer w hether the responsible genetic lesion is inherited (primary) or somatic (se condary). To address this question, we identified a family in which multipl e members over three generations are affected with PD through exclusively m aternal lines. Cytoplasmic hybrids (cybrids) were created for 15 family mem bers over two generations by transferring each individual's mtDNA to mtDNA- depleted human neuroblastoma cells. Eight of the 15 cybrid lines contained mtDNA obtained from maternally descended family members and seven contained mtDNA from paternally descended family members. After 6 weeks of culture, cybrid cell lines were assayed for complex I activity and oxidative stress, and mitochondrial morphology was analyzed by electron microscopy. Compared with the cybrid lines containing mtDNA from paternal descendants, cybrid l ines containing mtDNA from maternal descendants had lower complex I activit y, increased reactive oxygen species production, increased radical scavengi ng enzyme activities, and more abnormal mitochondrial morphologic features. These findings were present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal de scendants, and support a precedent far inherited mtDNA mutation in some per sons with PD.