A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer's disease.

Autor: García-Escudero V; Departamento de Anatomía, Histología y Neurociencia, School of Medicine, Autonoma de Madrid University (UAM), Arzobispo Morcillo, 4, 28029, Madrid, Spain.; Graduate Program in Neuroscience, Autonoma de Madrid University (UAM), Arzobispo Morcillo, 4, 28029, Madrid, Spain.; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., Ruiz-Gabarre D; Departamento de Anatomía, Histología y Neurociencia, School of Medicine, Autonoma de Madrid University (UAM), Arzobispo Morcillo, 4, 28029, Madrid, Spain.; Graduate Program in Neuroscience, Autonoma de Madrid University (UAM), Arzobispo Morcillo, 4, 28029, Madrid, Spain.; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., Gargini R; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain.; Neurooncology Unit, Instituto de Salud Carlos III-UFIEC, 28220, Madrid, Spain., Pérez M; Departamento de Anatomía, Histología y Neurociencia, School of Medicine, Autonoma de Madrid University (UAM), Arzobispo Morcillo, 4, 28029, Madrid, Spain.; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., García E; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., Cuadros R; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., Hernández IH; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain., Cabrera JR; Unidad de Investigación, Fundación Hospital de Jove, 33290, Gijón, Spain., García-Escudero R; Molecular Oncology Unit, CIEMAT, Ave Complutense, 40, 28040, Madrid, Spain.; Hospital 12 Octubre Research Institute/CIEMAT, Madrid, Spain.; Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Valderrebollo, 5, 28031, Madrid, Spain., Lucas JJ; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28031, Madrid, Spain., Hernández F; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28031, Madrid, Spain., Ávila J; Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain. javila@cbm.csic.es.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28031, Madrid, Spain. javila@cbm.csic.es.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2021 Jul; Vol. 142 (1), pp. 159-177. Date of Electronic Publication: 2021 May 02.
DOI: 10.1007/s00401-021-02317-z
Abstrakt: Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer's patients' brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer's disease and other tauopathies.
Databáze: MEDLINE
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