Is Somatic Mosaicism in Brain Tissue an Important Contribution to Neurodegeneration?

Somatic mosicism is a description of the pattern of different collections of mutations throughout the cells of a tissue. The vast majority of any given tissue is made up of somatic cells. These cells are limited in the number of times they can divide; initially created with long telomeres, they lose a little of their telomere length with each cell division. With short enough telomeres, the Hayflick limit is reached and cells become senescent and destroy themselves, or are destroyed by the immune system. New somatic cells with long telomeres, to replace the losses, are provided by the activity of much smaller populations of stem cells or progenitor cells. Thus any given tissue is in a state of turnover, though at a very different pace. The central nervous system has very little turnover, and many cells last a lifetime. The lining of the intestine turns over in a matter of days.

Mutations accumulate in cells constantly, but the vast majority are apparently harmless, at least over the timescale of the present human life span. Even if a mutation is problematic for cell function, and provided that it does not promotes cancerous behavior, then just how much damage can it do? When somatic cells become mutated in non-cancerous ways, that mutation will not spread far, since such cells are limited in the number of times they can divide. When stem cells or progenitor cells become mutated, however, there is the potential for mutations to become widely dispersed throughout a tissue. This is particularly true for the mutations that occur during embryonic development or in childhood. Those seem likely to be more influential in the brain, as only during development is there significant deployment of new cells.

There is an ongoing debate over the degree to which non-cancerous mutations to nuclear DNA contribute to degenerative aging. The expansion of mutations, via the processes noted above, to form somatic mosaicism is an important part of that debate, as illustrated by today's research materials. This is novel in the research I've seen on this topic, in that the absence of mosaicism is the interesting point. Younger people have more mosaicism in the brain than older people, at least in the few samples examined here. That suggests that cells with mutations are dying off on the way to old age, which in turn suggests a contribution to the processes of age-related neurodegeneration.

So far, however, I would say that there is no good evidence for raised rates of non-cancerous mutation to do all that much in animal studies, which suggests that perhaps this sort of molecular damage isn't as important as the other various forms of cell and tissue damage outlined in the SENS rejuvenation research proposals. Clearly at some point one must reach a harmful threshold of cellular dysfunction due to mutational damage, but the individuals of any given mammalian species may or may not be close to that point in later life. The presence of all of the other damage and dysfunction of aging obscures this specific contribution, and no-one has yet come up with a truly compelling, definitive way to isolate just non-cancerous mutational damage to nuclear DNA in a study.

Discovery May Explain a Great Mystery of Alzheimer's, Parkinson's

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.

The finding emerged unexpectedly from investigations into schizophrenia. It was in that context that 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. Researchers 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. Based on the finding, 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.

Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex

Neocortical neurons are among the most diverse and longest-lived mammalian cells. Every human neocortical neuron may contain private somatic variants. Single nucleotide variants (SNVs) are especially common, with hundreds per neuron reported, and with frequencies of more than 3,000 SNVs per neuron observed in aged individuals. Endogenous mobile elements such as retrotransposons are also active during brain development. Mobile element activity has been linked to the generation of copy-number variants (CNVs). By contrast to other somatic variants, large CNVs almost always affect multiple genes. A reanalysis of published data herein found an average of 63 genes affected per neuronal CNV.

The most salient feature of the brain CNV atlas that we have produced is an anti-correlation between the age of an individual and the percentage of CNV neurons in the frontal cortex of that individual. By contrast, the initial assessment of CNV location finds evidence for the enrichment of a subset of long genes and neurally associated gene ontology categories only in aged brains. Given the enrichment of these CNVs in aged, not young, neurons, CNVs affecting some genomic loci may be more compatible with neural survival than others. We found similar rates of CNV non-neurons at different ages; however, it will be interesting to determine whether other long-lived cells (e.g., cardiomyocytes) show a similar change in mosaic composition during aging.

We provide evidence that a functional consequence of CNV neurons may be selective vulnerability to aging-related cell death. Age-related cognitive decline is associated with notable decreases in cerebral cortical thickness, myelination, and synapse number accompanied by ex vacuo enlargement in ventricular volume. Although neuronal cell death is generally considered to be minimal in the healthy mature brain, rates of ∼10% cerebral cortical neuron loss during adulthood are consistent with stereological counts in neurotypical individuals. The decline in CNV neuron prevalence that we observe between individuals younger than 30 years old and individuals older than 70 years old is also strikingly consistent with selective CNV neuron loss during a person's adult lifetime. We conclude that the most parsimonious interpretation of these data is that many, but not all, CNV neurons are selectively vulnerable to aging-associated atrophy.

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