|Alzheimer > 10. miR-132 Deficiency Increases Total and 4R-Tau Level|
In a healthy adult human brain, the levels of 4-repeat (4R) and 3-repeat (3R) Tau proteins are approximately equal. The previous chapter has explained how elevated total and/or 4R-Tau level may result in hyperexcitability, This chapter will discuss how the total and 4R-Tau protein is regulated.
As described in Chapter 5, Tau isoforms are produced from a single gene through alternative RNA splicing. The 4R-Tau includes the repeat encoded by exon 10. Recently, microRNAs have been demonstrated to play important roles in the regulation of gene expression. A microRNA is a small non-coding RNA molecule (~ 22 nucleotides), generated from the genomic DNA. To date, over 2000 microRNAs have been discovered in humans (Hammond, 2015). They are named with the prefix "miR" followed by a dash and a number. A suffix, -3p or -5p, may also be included, specifying whether the mature microRNA originates from the 3' or 5' arm of its precursor.
The mature microRNA interacts with its target (the mRNA of a protein) within a structure called RNA-induced silencing complex (RISC). For perfect or nearly perfect complementarity between a microRNA and its mRNA target, the interaction within RISC will result in mRNA degradation. For partial complementarity, the translation of the target mRNA will be repressed (Ye et al., 2016).
miR-132 targets the mRNA of both Tau protein and a splicing factor, polypyrimidine tract-binding protein 2 (PTBP2). Thus, miR-132 regulates not only the total Tau protein level, but also the ratio between 4R and 3R Tau proteins. miR-132 deficiency has been shown to increase total Tau expression and the 4R:3R Tau ratio (Smith et al., 2011; Smith et al., 2015). It is implicated in Alzheimer's disease (Hébert et al., 2013; Lau et al., 2013), and other tauopathies such as progressive supranuclear palsy (Smith et al., 2011) and Huntington's disease (Johnson and Buckley, 2009).
Author: Frank Lee