title: 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.
authors.affiliation: Centre de recherche du CHUQ, Axe Neurosciences, Québec, Canada.
authors.forename: Pascal Y
authors.initials: PY
authors.lastname: Smith
authors.forename: Charlotte
authors.initials: C
authors.lastname: Delay
authors.forename: Johanne
authors.initials: J
authors.lastname: Girard
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
mesh_terms: D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C504334:PTBP2 protein, human; D020033:Protein Isoforms; D016875:tau Proteins; D038941:Polypyrimidine Tract-Binding Protein