Somatic Mosaicism in the Aging Brain
Mutations in stem cell populations can spread throughout a tissue, and the occurrence of mutations over time leads to a pattern of mutations known as somatic mosiacism. Most mutations cause little to no functional change in the cells in which they occur, as most of the genome is dormant. Does somatic mosaicism provide a significant contribution to degenerative aging due to the few mutations that do cause functional change and spread throughout tissues? There are only a few definitive correlations to date, but we might expect more to emerge as researchers continue to investigate. The brain is an interesting case, as neurons do suffer random mutations, but they are long-lived and rarely replaced. It is the supporting cells of the brain in which we might expect to see age-related somatic mosaicism similar to that occurring elsewhere in the body.
Every cell in the human brain possesses a unique genome that is the product of the accumulation of somatic mutations starting from the first postzygotic cell division and continuing throughout life. Somatic mosaicism in the human brain has been the focus of several recent efforts that took advantage of key technological innovations to start elucidating brain development, aging, and disease directly in human tissue. On one side, somatic mutation occurring in progenitor cells has been used as a natural barcoding system to address cell phylogenies of clone formation and cell segregation in the brain lineage. On the other side, analyses of mutation rates and patterns in the genome of brain cells have revealed mechanisms of brain aging and disorder predisposition.
Accumulation of somatic mutations in aging brain cells informs on cell-type-specific disease predisposition. Somatic mutation in neurons is linked to neurodegeneration. In glial cells, however, somatic mutation may play a role in predisposing to tumor insurgence as we become older. Since there is very little neuronal turnover in the postnatal brain, clonal expansions are either congenital or the product of postnatal expansions within the glia lineage. Indeed, an increase in clonal oncogenic somatic mutations was observed in the white matter of the normal human cerebral cortex compared to the adjacent grey matter.
Recent studies have shown how certain pathological states are associated to increased somatic mutation rates in the human brain and to disease-specific mechanisms. Although current knowledge seems to suggest that increased somatic mutation in Alzheimer's disease is due to oxidative damage due to the disorder, the exact role of increased rates of somatic mutation in neurodegeneration remains unclear, as well as the limit beyond which somatic mutations are not tolerated, thus leading to cell death.
Has anyone looked at this in mitochondria?