Genes in brain cells are not identical!

One of the great mysteries of neuroscience may finally have an answer: Scientists have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer's, Parkinson's and other neurodegenerative diseases.

The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation - called "somatic mosaicism" - could explain why neurons in the temporal lobe are the first to die in Alzheimer's, for example, and why dopaminergic neurons are the first to die in Parkinson's.

"This has been a big open question in neuroscience, particularly in various neurodegenerative diseases," said the senior author. "What is this selective vulnerability? What underlies it? And so now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in young individuals and that sets up different regions for decline later in life."

The finding emerged unexpectedly from the investigations into schizophrenia. It was in that context that the researchers first discovered the unexpected variation in the genetic makeup of individual brain cells. That discovery may help explain not just schizophrenia but depression, bipolar disorder, autism and other conditions.

Continuing the investigations, the authors expected that this mosaicism would increase with age - that mutations would accumulate over time. What they found is exactly the opposite: Younger people had the most mosaicism and older people had the least.

"We wound up building an atlas that contained neurons from 15 individuals. None of these individuals had disease," said the author. "They ranged in age from less than a year to 94 years, and it showed a perfect correlation - a perfect anti-correlation - with age."

Based on the finding, the researchers believe that the neurons with significant genetic variation, known as CNV neurons, may be the most vulnerable to dying. And that could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the most CNV neurons in the temporal lobe, for example, might be likely to develop Alzheimer's.

More work needs to be done to fully understand what's occurring, the author said. So far, they have only looked at neurons in the frontal cortex of the brain, and his studies are limited by the fact that neurons can be examined only after death, so it can be hard to make direct comparisons.

"What's really interesting about mosaicism is that it is fundamentally tweaking our assumptions about what nature is, because we've kind of always assumed that every cell in any given individual had the same genome, the same DNA in every cell," the author said. "And now we're showing that it's different and what that might mean."