2024-03-28T19:14:08Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/132142024-01-09T10:51:21Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2109com_20.500.12105_2052col_20.500.12105_16938col_20.500.12105_2110
Repisalud
author
García-Escudero, Vega
author
Ruiz-Gabarre, Daniel
author
Gargini, Ricardo
author
Pérez, Mar
author
García, Esther
author
Cuadros, Raquel
author
Hernández, Ivó H
author
Cabrera, Jorge R
author
García-Escudero, Ramón
author
Lucas, José J
author
Hernández, Félix
author
Ávila, Jesús
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación Ramón Areces
funder
Banco Santander
funder
Asociación Española Contra el Cáncer
2021-06-29T19:17:09Z
2021-06-29T19:17:09Z
2021-07
Acta Neuropathol. 2021 Jul;142(1):159-177.
http://hdl.handle.net/20.500.12105/13214
33934221
10.1007/s00401-021-02317-z
1432-0533
Acta Neuropathologica
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.
eng
Alternative splicing
Alzheimer’s disease
Intron retention
Tau
Tauopathie
Truncation
A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer's disease
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/13214/1/ANewNonAggregative_2021.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/13214/7/ANewNonAggregativeSupplementaryInformation_2021.pdf.txt
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