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Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady

BACKGROUND: Mutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4–6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several followi...

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Autores principales: Shematorova, Elena K., Shpakovski, Dmitry G., Chernysheva, Anna D., Shpakovski, George V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889328/
https://www.ncbi.nlm.nih.gov/pubmed/30621751
http://dx.doi.org/10.1186/s13062-018-0212-y
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author Shematorova, Elena K.
Shpakovski, Dmitry G.
Chernysheva, Anna D.
Shpakovski, George V.
author_facet Shematorova, Elena K.
Shpakovski, Dmitry G.
Chernysheva, Anna D.
Shpakovski, George V.
author_sort Shematorova, Elena K.
collection PubMed
description BACKGROUND: Mutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4–6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several following years. Most JNCL patients carry the same 1.02-kb deletion in the CLN3 gene, encoding an unusual transmembrane protein, CLN3 or battenin. RESULTS: Based on data of genome-wide expression profiling in CLN3 patients with different rate of the disease progression [Mol. Med., 2011, 17: 1253–1261] and our bioinformatic analysis of battenin protein-protein interactions in neurons we propose that CLN3 can function as a molecular chaperone for some plasma membrane proteins, being crucially important for their correct folding in endoplasmic reticulum. Changes in spatial structure of these membrane proteins lead to transactivation of the located nearby receptors. Particularly, CLN3 interacts with a subunit of Na/K ATPase ATP1A1 which changes its conformation and activates the adjacent epidermal growth factor receptor (EGFR). As a result, a large amount of erroneously activated EGFR generates MAPK signal cascades (ERK1/ERK2, JNKs and p38) from cell surface eventually causing neurons’ death. CONCLUSIONS: Molecular mechanism of the juvenile form of Batten disease (JNCL), which is based on the excessive activation of signaling cascades in a time of the radical increase of neuronal membranes’ area in the growing brain, have been proposed and substantiated. The primary cause of this phenomenon is the defective function of the CLN3 protein that could not act properly as molecular chaperone for some plasma membrane proteins in the endoplasmic reticulum. The incorrect three-dimensional structure of at least one such protein, ATP1A1, leads to unregulated spontaneous and repetitive activation of the SRC kinase that transactivates EGFR with the subsequent uncontrolled launch of various MAPK cascades. Possible ways of treatment of patients with JNCL have been suggested. REVIEWERS: This article was reviewed by Konstantinos Lefkimmiatis, Eugene Koonin and Vladimir Poroikov.
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spelling pubmed-68893282019-12-11 Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady Shematorova, Elena K. Shpakovski, Dmitry G. Chernysheva, Anna D. Shpakovski, George V. Biol Direct Hypothesis BACKGROUND: Mutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4–6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several following years. Most JNCL patients carry the same 1.02-kb deletion in the CLN3 gene, encoding an unusual transmembrane protein, CLN3 or battenin. RESULTS: Based on data of genome-wide expression profiling in CLN3 patients with different rate of the disease progression [Mol. Med., 2011, 17: 1253–1261] and our bioinformatic analysis of battenin protein-protein interactions in neurons we propose that CLN3 can function as a molecular chaperone for some plasma membrane proteins, being crucially important for their correct folding in endoplasmic reticulum. Changes in spatial structure of these membrane proteins lead to transactivation of the located nearby receptors. Particularly, CLN3 interacts with a subunit of Na/K ATPase ATP1A1 which changes its conformation and activates the adjacent epidermal growth factor receptor (EGFR). As a result, a large amount of erroneously activated EGFR generates MAPK signal cascades (ERK1/ERK2, JNKs and p38) from cell surface eventually causing neurons’ death. CONCLUSIONS: Molecular mechanism of the juvenile form of Batten disease (JNCL), which is based on the excessive activation of signaling cascades in a time of the radical increase of neuronal membranes’ area in the growing brain, have been proposed and substantiated. The primary cause of this phenomenon is the defective function of the CLN3 protein that could not act properly as molecular chaperone for some plasma membrane proteins in the endoplasmic reticulum. The incorrect three-dimensional structure of at least one such protein, ATP1A1, leads to unregulated spontaneous and repetitive activation of the SRC kinase that transactivates EGFR with the subsequent uncontrolled launch of various MAPK cascades. Possible ways of treatment of patients with JNCL have been suggested. REVIEWERS: This article was reviewed by Konstantinos Lefkimmiatis, Eugene Koonin and Vladimir Poroikov. BioMed Central 2018-09-25 /pmc/articles/PMC6889328/ /pubmed/30621751 http://dx.doi.org/10.1186/s13062-018-0212-y Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Hypothesis
Shematorova, Elena K.
Shpakovski, Dmitry G.
Chernysheva, Anna D.
Shpakovski, George V.
Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title_full Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title_fullStr Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title_full_unstemmed Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title_short Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady
title_sort molecular mechanisms of the juvenile form of batten disease: important role of mapk signaling pathways (erk1/erk2, jnk and p38) in pathogenesis of the malady
topic Hypothesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889328/
https://www.ncbi.nlm.nih.gov/pubmed/30621751
http://dx.doi.org/10.1186/s13062-018-0212-y
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