Long Non-Coding RNA in the Aging Brain
The first step of gene expression, the process of producing proteins from the genetic blueprint of DNA, is the production of an RNA molecule. This RNA is then used as an intermediary working model from which the final protein is produced. Non-coding RNA molecules are those that do not translate into a protein, but otherwise serve one of a wide variety of purposes in the cell. Many of these non-coding RNA molecules are in some way involved in regulating gene expression; the production of proteins in a cell is a highly complex, many-layered, and dynamic collection of processes. It is also far from being completely mapped in detail in its youthful, fully functional state, never mind the countless changes to that state that take place in reaction to the accumulating molecular damage of aging. There is much yet to be discovered about the roles played by specific RNA molecules in cellular metabolism and its alterations over the course of aging.
Alterations in the aging brain include changes in the epigenetics and transcription of both coding and non-coding regions of the genome. Among non-coding transcripts, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of the molecular processes that underlie age-associated phenotypes. lncRNAs are transcripts that are longer than 200 nucleotides in length with virtually no protein-coding capacity. These transcripts are mostly uniquely expressed in cell types - both spatially and temporally - and are particularly enriched in the brain, where they play functional roles in neuroplasticity, cognition, and differentiation of neural stem cells. Additionally, lncRNAs are known to orchestrate epigenetic processes through their interactions with epigenetic machinery.
This review proposes ways by which lncRNAs may contribute to neural aging and how their functions can be altered across the human lifespan. We discuss that antisense lncRNAs can regulate pathological protein aggregation and that subnuclear compartment specific lncRNAs can regulate neuronal splicing, transcription, and sponging of ion channels in aging. Other pre- and post-transcriptional regulatory roles performed by lncRNAs are also discussed in the context of cognition, neurogenesis, and neurodegeneration in aging, including the possible influence of lncRNAs on the maintenance of the 3D nuclear architecture.
In summary, the coding/non-coding interactome that sustains important processes of cognition and adult neurogenesis may become compromised during neuronal aging. It is not yet known whether changes in the transcription of lncRNAs are reactive, compensatory, or causative of aging. However, rapidly accumulating evidence supports the vital contribution of lncRNAs in neuronal aging.