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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00004

TrkB-ICD fragment, originated from BDNF receptor cleavage, is translocated to cell nucleus and phosphorylates nuclear, somal and axonal proteins

 João F. Fonseca-Gomes1, 2*, André Jerónimo-Santos1, 2,  Angelina Lesnikova3, Plinio Casarotto3,  Eero Castren3, Ana M. Sebastião1, 2 and  Maria J. Diogenes1, 2
  • 1Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal
  • 2Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
  • 3Neuroscience Center, University of Helsinki, Finland

The signalling of Brain-Derived Neurotrophic Factor (BDNF) has been suggested to be impaired in Alzheimer´s disease (AD), which may compromise the function of BDNF upon neuronal activity and survival. Accordingly, decreased levels of BDNF and its TrkB Full-Length receptor (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to Aβ peptide, a hallmark of AD, leads to calpain overactivation and subsequent TrkB-FL cleavage leading to decreased levels of TrkB-FL and the generation of two new fragments: a membrane-bound truncated receptor (TrkB-T’) and an intracellular fragment (TrkB-ICD). Importantly, we identified this TrkB-FL cleavage and TrkB-ICD presence in human brain samples, which indicates that this molecular mechanism contributes to the loss of BDNF signalling in humans. The exact role of this TrkB-ICD fragment is, however, unknown. Here, we used a human neuroglioma cell line and rat cortical primary neuronal cultures to track TrkB-ICD intracellularly. Our data show that TrkB-ICD is a relatively stable fragment that accumulates in the nucleus over time, through a phosphorylation-dependent process. We also found that TrkB-ICD has tyrosine kinase activity, inducing the phosphorylation of nuclear and axonal proteins.
These findings suggest that TrkB-ICD may lead to a dysregulation of the activity of several proteins, including proteins in the nucleus, to where TrkB-ICD migrates. Since TrkB-ICD is formed by Aβ peptide-induced cleavage of TrkB-FL, the present data highlights a new mechanism that may have a role in AD pathophysiology.

Keywords: Alzheimer’s disease (AD), Brain-derived neurotrophic factor (BDNF), TrkB, excitotixicity, Neurodegeneration amyloid-beta, Neuroprotection, TrkB-ICD

Received: 10 Sep 2018; Accepted: 09 Jan 2019.

Edited by:

David Blum, INSERM U1172 Centre de Recherche Jean Pierre Aubert, France

Reviewed by:

Volkmar Lessmann, Medizinische Fakultät, Universitätsklinikum Magdeburg, Germany
Catarina A. Gomes, University of Coimbra, Portugal
Laurent Givalois, INSERM U1198 Mécanismes Moléculaires dans les Démences Neurodégénératives, France  

Copyright: © 2019 Fonseca-Gomes, Jerónimo-Santos, Lesnikova, Casarotto, Castren, Sebastião and Diogenes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. João F. Fonseca-Gomes, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, 1649-028, Lisbon, Portugal, jaofilipegomes@gmail.com