BioWorld International Correspondent
LONDON - Parkinson's disease, together with many symptoms of normal aging, may be due to genetic abnormalities in cellular organelles in a subset of brain neurons.
In a surprise discovery, researchers have found that the DNA of the mitochondria, which provide cells with energy, often is faulty in localized parts of the brain.
Douglass Turnbull, professor of neurology at the University of Newcastle upon Tyne in the UK, told BioWorld International, "We found that, in the part of the brain that suffers death of cells in Parkinson's disease, up to 50 percent of the mitochondrial DNA has large deletions, with the loss of several of the genes that are involved in cellular respiration."
Studies that looked at other tissues from elderly people identified similar abnormalities - but in those cells, fewer than 1 in 100 mitochondrial DNA molecules have been affected. "The level of loss we saw in our study was unprecedented," Turnbull said.
Turnbull's group focused on the part of the brain called the substantia nigra - Parkinson's disease is caused by the loss of the dopamine-producing cells that originate there. The symptoms of the disease include tremor and difficulty in initiating movement.
The condition is the second most common neurodegenerative disease after Alzheimer's disease, affecting between 1 percent and 2 percent of people older than 60. In addition, one in four of those older than 65 years, and one in two of those older than 85 years, have a less severe movement disorder called mild parkinsonian signs (MPS).
Turnbull and his colleagues already have embarked on finding out how the loss of mitochondrial DNA occurs. He said: "Many people have postulated that the cells may die because of oxidative damage. It's important that we understand the mechanism by which the mitochondrial DNA deletions occur. If it was due to oxidative damage, then it's possible that targeting antioxidants at these cells could prevent some of the symptoms."
An account of the findings appear in the May Nature Genetics in a paper titled "High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease."
A companion paper in the same issue of Nature Genetics describes finding high levels of mitochondrial DNA deletions in the substantia nigra of elderly people. Its title is "Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons."
Turnbull and his team decided to investigate mitochondria in depth because numerous earlier research studies hinted that mitochondria played a role in aging and Parkinson's disease.
Mitochondria are the cellular organelles responsible for respiration. They contain their own DNA. That encodes 13 proteins involved in mitochondrial respiration. Each mitochondrion has many copies of its DNA.
Turnbull and his colleagues first examined the activity of two enzymes that are involved in mitochondrial respiration. They found that the enzyme cytochrome c oxidase (COX) was more likely to be out of action in neurons from people who had suffered from Parkinson's disease than in neurons from controls.
The team then looked for point mutations in the mitochondrial DNA from the cells that were deficient in COX activity, but did not find any that were likely to be responsible for the defect.
Further investigations showed that some cells had mitochondrial DNA that had sections missing - and that the mitochondrial DNA deletions were, in each case, unique to the individual neurons.
The group next looked at the levels of deleted mitochondrial DNA in neurons with normal COX activity from the substantia nigra of people who had suffered Parkinson's disease and from controls. Levels of deleted mitochondrial DNA were very high in both groups, and statistically significantly higher than in neurons from the hippocampus of the brain.
There also was a highly statistically significant correlation between the amount of deleted mitochondrial DNA and increasing age.
Finally, the team looked at the level of deleted mitochondrial DNA in neurons with deficient COX activity and compared it with that in neurons with normal COX activity. The level was statistically significantly higher in the former than in the latter, and that confirms, the researchers said, that COX deficiency is indeed attributable to high levels of deleted mitochondrial DNA.