MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy

Abstract

Tauopathies represent a large class of neurological and movement disorders characterized by abnormal intracellular deposits of the microtubule-associated protein tau. It is now well established that mis-splicing of tau exon 10, causing an imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms, can cause disease; however, the underlying mechanisms affecting tau splicing in neurons remain poorly understood. The small noncoding microRNAs (miRNAs), known for their critical role in posttranscriptional gene expression regulation, are increasingly acknowledged as important regulators of alternative splicing. Here, we identified a number of brain miRNAs, including miR-124, miR-9, miR-132 and miR-137, which regulate 4R:3R-tau ratios in neuronal cells. Analysis of miRNA expression profiles from sporadic progressive supranuclear palsy (PSP) patients, a major 4R-tau tauopathy, showed that miR-132 is specifically down-regulated in disease. We demonstrate that miR-132 directly targets the neuronal splicing factor polypyrimidine tract-binding protein 2 (PTBP2), which protein levels were increased in PSP patients. miR-132 overexpression or PTBP2 knockdown similarly affected endogenous 4R:3R-tau ratios in neuronal cells. Finally, we provide evidence that miR-132 is inversely correlated with PTBP2 during post-natal brain development at the time when 4R-tau becomes expressed. Taken together, these results suggest that changes in the miR-132/PTBP2 pathway could contribute to the abnormal splicing of tau exon 10 in the brain, and sheds light into the potential role played by miRNAs in a subset of tauopathies.

microRNA profiling: increased expression of miR-147a and miR-518e in progressive supranuclear palsy (PSP)

“…We also found slightly decreased levels of miR-132, but the difference to controls was not significant. Our failure to detect a significant decrease in miR-132 may be due to the larger sample size (n = 20) of the present study as compared to that of Smith et al (n = 8) [19]. It cannot, however, be ascribed to the higher average age at death of controls as compared to PSP patients.…”

“…A recent study in eight PSP patients and eight controls found significantly (p < 0.01) decreased expression of miR-132 in brains from patients as compared to controls [19]. Temporal, parietal, and prefrontal lobe tissues were used for RNA extraction in the former study.…”

Memory formation and retention are affected in adult miR-132/212 knockout mice

“…RNU19 probe (#001003) was used as normalization control. Relative expression was calculated by the 2-CT method as before [30].…”

Decoding the non-coding RNAs in Alzheimer’s disease

“…Nevertheless, reducing global miRNA production by using a conditional knockout of Dicer in mouse brain induced changes in Tau metabolism including AD-like hyperphosphorylation and altered MAPT splicing [111,112]. Indeed, loss of neuronal dicer mimicked several AD phenotypes including progressive neurodegeneration, enlarged ventricles, reduced brain size, neuroinflammation and impaired dendritic branching and spine length [113,114].…”

“…Together, this indicates that proper regulation of MAPT splicing is important to maintain normal brain function. Smith et al [112] have shown that several brain miRNAs, including miR-124, -9, -132 and -137, can regulate the 4R/3R ratio in neuronal cells. Interestingly, both miR-9 and miR-124 are down-regulated in AD and could therefore contribute to an altered Tau composition in disease.…”