Introducing the brain: long-lived neurons (Introduction)

by David Turell , Friday, April 02, 2021, 14:57 (1329 days ago) @ David Turell

Only the hippocampus makes new neurons. This means the neurons that exist at puberty are there for life and must repair themselves throughout life. This study looks at DNA repair:

https://science.sciencemag.org/content/372/6537/91?intcmp=trendmd-sci

"DNA repair within neurons
Humans have only a limited capacity to generate new neurons. These cells thus need to repair errors in the genome. To better understand this process, Reid et al. developed Repair-seq, a method to locate DNA repair within the genome of stem cell–derived neurons. DNA repair hotspots (DRHs) were more likely to occur within specific genomic features such as gene bodies as well as in genomic formations, open chromatin, and active regulatory regions. This method showed that repair was enriched at sites involved in neuronal function and identity. Furthermore, proteomic data indicated that genes in DRHs are enriched in Alzheimer's disease and that DRHs are more active in aging. These observations link neuronal DNA repair to aging and neurodegeneration.

Science, this issue p. 91

"Abstract
Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

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"Our results suggest that DRHs are established in neurons and play a key role in identity and function. Going forward, Repair-seq will be a powerful tool to explore how age and disease disrupt genome integrity in the nervous system. Finally, whether DRHs are specific to neurons, particular developmental lineages, or other nondividing cells or are found in only some long-lived species remains an open question. The discovery of these sites in other cell types might further aid in our understanding of how age-related changes in their organization could drive differential aging or the development of disease in other tissue types."

Comment: as neurons drop away over a lifetime us old folks find it troublesome to find a specific word we want, but generally our thinking re mans quite clear and reaches reasonable results. But since overall numbers are necessary for all of life, this might explain why in evolution our brain was oversized early on with 150 cc of brain substance lost as we developed use of all its incipient functions. The most important and perhaps the most capable-at-surviving neurons were saved for a lifetime. Obvious design.