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

• Published in: Human molecular genetics Vol. 20; no. 20; pp. 4016 - 4024
• Main Authors: Smith, Pascal Y., Delay, Charlotte, Girard, Johanne, Papon, Marie-Amélie, Planel, Emmanuel, Sergeant, Nicolas, Buée, Luc, Hébert, Sébastien S.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15-10-2011
• Subjects: Aged; Alternative Splicing - genetics; Animals; Biological and medical sciences; Brain - metabolism; Cell Line, Tumor; Exons; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Medical sciences; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Molecular and cellular biology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oculomotor disorders; Ophthalmology; Polypyrimidine Tract-Binding Protein - genetics; Polypyrimidine Tract-Binding Protein - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Supranuclear Palsy, Progressive - genetics; tau Proteins - genetics; tau Proteins - metabolism; Nervous system diseases; RNA interference; Micro RNA; Supranuclear ophthalmoplegia; Cerebral disorder; Gene silencing; Eye disease; Exon; Tau protein; Central nervous system disease; Genetics; Degenerative disease; Oculomotor syndrome; Brain stem syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr330

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.