Naturally occurring gene variations in brain cells may explain why dopamine-producing neurons are the first to die in people with Parkinson’s, according to a new study.
The findings also suggest that brain regions with a greater number of these variations are more likely to undergo cell death later in life in distinct neurodegenerative diseases.
The research, “Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex,” was published in the scientific journal Cell Reports.
Unlike neuronal types, which are thought to be stable throughout life, the genetic makeup of nerve cells is variable. In the neocortex — a part of the cerebral cortex involved in functions such as sensory perception, motor function, thought, and language — the generation of copy-number variants (CNVs) due to imperfect DNA repair affects multiple genes and leads to significant diversity in a subset of neurons.
CNVs are genetic alterations where a certain section of the genome is repeated, making the number of repeats vary considerably among different neurons.
This genetic variation, called mosaicism, indicates the person is a mosaic — that is, composed of more than one genotype, or genetic constitution, although the person has developed from a single fertilized egg. In humans, all cells descending from the fusion of egg and sperm should contain an identical nuclear genome — our personal DNA signature.
“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,” Michael McConnell, PhD, the study’s senior author, said in a press release. “And now we’re showing that it’s different and what that might mean.”
The occurrence of CNVs during embryonic development has been associated with risk for schizophrenia, autism, and other neurological disorders. However, studies of CNVs specifically in nerve cells have not been able to determine whether the affected genes contribute to brain development, function, and disease.
“This has been a big open question in neuroscience, particularly in various neurodegenerative diseases,” McConnell said. “What is this selective vulnerability? What underlies it?”
Aiming to address these questions, scientists at the University of Virginia School of Medicine used a statistical analysis to assemble a brain atlas and assess how CNVs in neurons alter the genetic makeup of the human cerebral cortex.
Published data from 10 individuals were combined with a new dataset of over 800 neurons from five participants. All 15 individuals were healthy, ranging in age from one year to 95 years.
The results showed an atlas with 507 CNVs in nerve cells. It revealed that the frequency of neocortical neurons with complex karyotypes — the number and appearance of chromosomes in a cell — varies widely among individuals. Also, both the proportion of complex karyotypes and the size of CNVs were greater in neurons than in other cell types.
The investigators then found that younger individuals had more variations in neurons than older people. This was in contrast to the team’s hypothesis that this mosaicism would increase with age, or that mutations would accumulate over time due to aging-associated cellular alterations.
“It showed a perfect correlation — a perfect anti-correlation — with age,” McConnell said. “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.”
“This cross-sectional finding highlights the unmet need for an increased longitudinal understanding of human neuronal genome dynamics during an individual’s health span,” the scientists stated.
Looking ahead, the team will use a brain bank from the Lieber Institute to look at other brain areas, such as the temporal lobe, the site with the earliest neuronal death in Alzheimer’s. “So now I can really start to map things out more carefully, building an atlas of different brain regions from many individuals,” McConnell said.
https://parkinsonsnewstoday.com/2019/02/20/gene-variations-early-in-life-may-explain-vulnerability-to-neurodegenerative-diseases/
No comments:
Post a Comment