Mapping the course of neurodegeneration

Written by Jenny Straiton

New research provides a possible explanation as to why neurodegenerative disorders originate in one distinct region, answers that show potential for the development of new treatments.

Somatic mosaicism

In diseases such as Alzheimer’s and Parkinson’s, the progress of neurodegeneration follows a distinctive path, always starting in the same place; for Alzheimer’s it’s the temporal lobe, for Parkinson’s it’s the dopaminergic neurons of the substantia nigra.

Until now, the reason for this selective vulnerability has been unknown, as it had been assumed that brain cells were genetically identical.

“This has been a big open question in neuroscience, particularly in various neurodegenerative diseases,” commented neuroscientist Michael McConnell from the University of Virginia (VA, USA). “What is this selective vulnerability? What underlies it?”

During investigations into schizophrenia, the team from McConnell’s lab found individual brain cells to have variation in their genetic make-up, a discovery that may also help in explaining many other mental health disorders, including depression, bipolar and autism.

In a continuation of their investigation, the team were expecting to see an increase in variation with age as mutations accumulate over time. However, they were surprised to find the opposite result; older individuals had less variability, also known as somatic mosaicism, than younger.

“What’s really interesting about mosaicism is that it is fundamentally tweaking our assumptions about what nature is”

“We wound up building an atlas that contained neurons from 15 individuals. None of these individuals had disease,” explained McConnell. “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 upon these results, that were recently published in Cell Reports, McConnell believes that the neurons with significant genetic variation could be more vulnerable to dying than those without. This may provide an explanation for the idiosyncratic death of selective neurons in the development of different neurodegenerative diseases, as well as why certain people would be more likely to have the diseases than others; those with more of the neurons with significant variation, known as CNV neurons, in the temporal lobe would be more likely to develop Alzheimer’s.

As of now, studies are limited by the fact that neurons can only be examined post-mortem, therefore making it difficult to make direct comparisons. Also, the current work has been focused on the frontal cortex of the brain, so more research is needed in order to fully understand what is occurring.

“Because I’m collaborating with the Lieber Institute (MD, USA) and they have this fantastic brain bank, now I can look at individuals’ frontal cortex for the schizophrenia research and I can look at the temporal lobe in those same individuals,” commented McConnell. “So now I can really start to map things out more carefully, building an atlas of different brain regions from many individuals.”

With further research this could greatly advance understanding in regard to both neurodegenerative diseases as well as the cognitive decline that comes with them, potentially leading to the development of new treatments.

“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,” he concluded. “And now we’re showing that it’s different and what that might mean.”