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

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Fonseca-Gomes , J , Jerónimo-Santos , A , Lesnikova , A , Casarotto , P , Castrén , E , Sebastião , A M & Diógenes , M J 2019 , ' TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins ' , Frontiers in Molecular Neuroscience , vol. 12 , 4 . https://doi.org/10.3389/fnmol.2019.00004

Title: TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins
Author: Fonseca-Gomes, João; Jerónimo-Santos, André; Lesnikova, Angelina; Casarotto, Plinio; Castrén, Eero; Sebastião, Ana M.; Diógenes, Maria J.
Contributor: University of Helsinki, Neuroscience Center
University of Helsinki, Neuroscience Center
University of Helsinki, Neuroscience Center
Date: 2019-02-01
Language: eng
Number of pages: 8
Belongs to series: Frontiers in Molecular Neuroscience
ISSN: 1662-5099
URI: http://hdl.handle.net/10138/312734
Abstract: The signaling 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 tropomyosin-receptor kinase B-full-length (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to amyloid-beta (A beta) 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 signaling 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 A beta peptide-induced cleavage of TrkB-FL, the present data highlights a new mechanism that may have a role in AD pathophysiology.
Subject: Alzheimer's disease
CORTEX
DISEASE
LENGTH
NEUROTROPHIC FACTOR
TrkB-FL cleavage
TrkB-ICD fragment
brain-derived neurotrophic factor
excitotoxicity
neurodegeneration
neuroprotection
3112 Neurosciences
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