One of the great mysteries of neuroscience may finally have an answer: Scientists from the University of Virginia's Faculty of Medicine have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer's disease , Parkinson's and other neurodegenerative diseases.
The new research suggests that cells can die due to the natural variation of genes in brain cells, which were, until recently, assumed to be genetically identical. This variation – called "somatic mosaicism" – could explain why temporal lobe neurons are the first to die in Alzheimer's disease, for example, and why dopaminergic neurons are the first to die in Parkinson's disease.
"This has been a big open question in neuroscience, especially in various neurodegenerative diseases," said neuroscientist Michael McConnell, PhD, of the Brain Immunology Research Center and Glia (BIG) of the UVA. "What is this selective vulnerability? What underpins it? And now, with our work, the hypotheses that are advancing are that it could be that different brain regions actually have a different garden than these [variations] among young people and setting up different regions for decline later in life ".
An unexpected result
The discovery came unexpectedly in McConnell's schizophrenia investigations. It is in this context that he and his colleagues for the first time discovered the unexpected variation in genetic makeup of individual brain cells. This discovery may help explain not only schizophrenia, but also depression, bipolar disorder, autism and other conditions.
Continuing his research, McConnell expected this mosaicism to increase with age – mutations accumulate over time. What he and his colleagues at Johns Hopkins discovered is exactly the opposite: the youngest had the most mosaicism and the oldest the least.
"We ended up building an atlas containing neurons of 15. None of these people had any disease," said McConnell of the Department of Biochemistry and Molecular Genetics and the Department of Neuroscience. ; UVA. "Their age ranged from less than a year to 94 years and this showed a perfect correlation – a perfect anti-correlation – with age."
Based on this discovery, McConnell believes that neurons with significant genetic variation, called CNV neurons, are perhaps the most vulnerable to death. And this could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the largest number of CNV neurons in the temporal lobe, for example, are at risk of developing Alzheimer's disease.
McConnell said that there was still a lot of work to do to fully understand what was happening. Until now, he has only examined the neurons of the frontal cortex of the brain and his studies are limited by the fact that neurons can only be examined after death, so it is difficult to make direct comparisons. But he is enthusiastic about expanding his field of research.
"As I collaborate with the Lieber Institute and this brain bank is fantastic, I can now examine the frontal cortex of individuals [for the schizophrenia research] and I can look at the temporal lobe in those same individuals, "McConnell said. So now, I can really begin to map things in more detail, by building an atlas of different brain regions of many individuals. "
This research could significantly advance our understanding of the neurodegenerative diseases and cognitive decline that beset us as we age, leading to new treatments.
"What's really interesting about mosaicism is that it fundamentally changes our assumptions about what nature is, because we've always assumed that every cell of an individual had the same genome, the same DNA in every cell, "said McConnell. "And now we show that it's different and what it could mean."
The researchers published their results in the scientific journal Cell reports. The research team consisted of William D. Chronister, Ian E. Burbulis, Margaret B. Wierman, Matthew J. Wolpert, Mark F. Haakenson, Aiden Smith CB, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger and Stefan Bekiranov and McConnell.
The work was funded by the National Institutes of Health, grants U01 MH106882, U01 MH106893, U01 MH106882-03S1 and T32 GM008136-30; and the McDonnell Foundation.
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