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J Alzheimers Dis. 2015;43(3):915-26. doi: 10.3233/JAD-140996.

N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization.

Author information

1
Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
2
Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic AXON Neuroscience SE, Bratislava, Slovak Republic.

Abstract

Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer's disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions. In our study, we demonstrate that truncated Tau151-391/4R changes its usual behavior and gains constitutive access into the nucleus of both primary rat neurons and human neuroblastoma cells. Our results show that partial/dysregulated nuclear localization of tau results from the removal of the N-terminal (1-150) residues of the protein. Data obtained by cell fractionation data were supported by confocal microscopy analysis of GFP-fused tau proteins. Furthermore, neither addition of the fusion protein, nor increased tau phosphorylation had any effect on the intracellular distribution of truncated tau. Our data further suggest that differential tau phospho-status between cytosolic and nuclear fractions is rather a consequence than a cause of truncated tau nuclear localization. Finally, truncated tau in the nucleus is engaged in interactions with subnuclear structure(s), since it exhibits reduced mobility. We conclude that N-terminal truncation of tau proteins leads to their nonphysiological subcellular distribution as a result of modified tau conformation.

KEYWORDS:

Alzheimer's disease; cell compartmentation; cell nucleus; neurodegenerative diseases; tau proteins; truncation

PMID:
25147106
DOI:
10.3233/JAD-140996
[Indexed for MEDLINE]

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