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MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies

BACKGROUND: The progression of Alzheimer’s disease (AD) is associated with an increase of phosphorylated tau in the brain. One of the earliest phosphorylated sites on tau is Ser(262) that is preferentially phosphorylated by microtubule affinity regulating kinase (MARK), of which four isoforms exist....

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Autores principales: Lund, Harald, Gustafsson, Elin, Svensson, Anne, Nilsson, Maria, Berg, Margareta, Sunnemark, Dan, von Euler, Gabriel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046661/
https://www.ncbi.nlm.nih.gov/pubmed/24533944
http://dx.doi.org/10.1186/2051-5960-2-22
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author Lund, Harald
Gustafsson, Elin
Svensson, Anne
Nilsson, Maria
Berg, Margareta
Sunnemark, Dan
von Euler, Gabriel
author_facet Lund, Harald
Gustafsson, Elin
Svensson, Anne
Nilsson, Maria
Berg, Margareta
Sunnemark, Dan
von Euler, Gabriel
author_sort Lund, Harald
collection PubMed
description BACKGROUND: The progression of Alzheimer’s disease (AD) is associated with an increase of phosphorylated tau in the brain. One of the earliest phosphorylated sites on tau is Ser(262) that is preferentially phosphorylated by microtubule affinity regulating kinase (MARK), of which four isoforms exist. Herein we investigated the expression of MARK1-4 in the hippocampus of non-demented elderly (NDE) and AD cases. RESULTS: In situ hybridization revealed a uniform, neuronal distribution of all four isoform mRNAs in NDE and AD. Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser(262) in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. In contrast MARK4 is largely absent in the neuronal cytoplasm. MARK3 was localized to a subset of the GVD-containing neurons and also had a weak general cytoplasmic neuronal staining in both NDE and AD. These results suggest that in AD, phosphorylated MARK3 and MARK4 are sequestered and proteolysed in GVDs. MARK1 and MARK2 were absent in GVDs and exhibited relatively uniform neuronal expressions with no apparent differences between NDE and AD. CONCLUSION: We found that the phosphorylated and fragmented forms of MARK4 and to some extent MARK3 are present in GVDs in AD, and that this expression is highly correlated with phosphorylation of tau at Ser(262). This may represent a cellular defense mechanism to remove activated MARK and p-tau Ser(262) from the cytosol, thereby reducing the phosphorylating effect on tau Ser(262) that appears to be a critical step for subsequent neurodegeneration.
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spelling pubmed-40466612014-06-06 MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies Lund, Harald Gustafsson, Elin Svensson, Anne Nilsson, Maria Berg, Margareta Sunnemark, Dan von Euler, Gabriel Acta Neuropathol Commun Research BACKGROUND: The progression of Alzheimer’s disease (AD) is associated with an increase of phosphorylated tau in the brain. One of the earliest phosphorylated sites on tau is Ser(262) that is preferentially phosphorylated by microtubule affinity regulating kinase (MARK), of which four isoforms exist. Herein we investigated the expression of MARK1-4 in the hippocampus of non-demented elderly (NDE) and AD cases. RESULTS: In situ hybridization revealed a uniform, neuronal distribution of all four isoform mRNAs in NDE and AD. Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser(262) in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. In contrast MARK4 is largely absent in the neuronal cytoplasm. MARK3 was localized to a subset of the GVD-containing neurons and also had a weak general cytoplasmic neuronal staining in both NDE and AD. These results suggest that in AD, phosphorylated MARK3 and MARK4 are sequestered and proteolysed in GVDs. MARK1 and MARK2 were absent in GVDs and exhibited relatively uniform neuronal expressions with no apparent differences between NDE and AD. CONCLUSION: We found that the phosphorylated and fragmented forms of MARK4 and to some extent MARK3 are present in GVDs in AD, and that this expression is highly correlated with phosphorylation of tau at Ser(262). This may represent a cellular defense mechanism to remove activated MARK and p-tau Ser(262) from the cytosol, thereby reducing the phosphorylating effect on tau Ser(262) that appears to be a critical step for subsequent neurodegeneration. BioMed Central 2014-02-17 /pmc/articles/PMC4046661/ /pubmed/24533944 http://dx.doi.org/10.1186/2051-5960-2-22 Text en © Lund et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 Research
Lund, Harald
Gustafsson, Elin
Svensson, Anne
Nilsson, Maria
Berg, Margareta
Sunnemark, Dan
von Euler, Gabriel
MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title_full MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title_fullStr MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title_full_unstemmed MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title_short MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies
title_sort mark4 and mark3 associate with early tau phosphorylation in alzheimer’s disease granulovacuolar degeneration bodies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046661/
https://www.ncbi.nlm.nih.gov/pubmed/24533944
http://dx.doi.org/10.1186/2051-5960-2-22
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