TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins

João Fonseca-Gomes, André Jerónimo-Santos, Angelina Lesnikova, Plinio Casarotto, Eero Castrén, Ana M. Sebastião, Maria J. Diógenes

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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.
Original languageEnglish
JournalFrontiers in Molecular Neuroscience
Volume12
ISSN1662-5099
DOIs
Publication statusPublished - 1 Feb 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3112 Neurosciences

Cite this

@article{4774e5b140594001827de49f5c9f1318,
title = "TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins",
abstract = "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 = "3112 Neurosciences",
author = "Jo{\~a}o Fonseca-Gomes and Andr{\'e} Jer{\'o}nimo-Santos and Angelina Lesnikova and Plinio Casarotto and Eero Castr{\'e}n and Sebasti{\~a}o, {Ana M.} and Di{\'o}genes, {Maria J.}",
year = "2019",
month = "2",
day = "1",
doi = "10.3389/fnmol.2019.00004",
language = "English",
volume = "12",
journal = "Frontiers in Molecular Neuroscience",
issn = "1662-5099",
publisher = "Frontiers Media",

}

TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins. / Fonseca-Gomes, João; Jerónimo-Santos, André; Lesnikova, Angelina; Casarotto, Plinio; Castrén, Eero; Sebastião, Ana M.; Diógenes, Maria J.

In: Frontiers in Molecular Neuroscience, Vol. 12, 01.02.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins

AU - Fonseca-Gomes, João

AU - Jerónimo-Santos, André

AU - Lesnikova, Angelina

AU - Casarotto, Plinio

AU - Castrén, Eero

AU - Sebastião, Ana M.

AU - Diógenes, Maria J.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - 3112 Neurosciences

U2 - 10.3389/fnmol.2019.00004

DO - 10.3389/fnmol.2019.00004

M3 - Article

VL - 12

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

SN - 1662-5099

ER -