Loughborough University
Leicestershire, UK
LE11 3TU
+44 (0)1509 263171
Loughborough University

Loughborough University Institutional Repository

Please use this identifier to cite or link to this item: https://dspace.lboro.ac.uk/2134/16864

Title: Phosphorylation inhibits turnover of the tau protein by the proteasome: Influence of RCAN1 and oxidative stress
Authors: Poppek, Diana
Keck, Susi
Ermak, Gennady
Jung, Tobias
Stolzing, Alexandra
Ullrich, Oliver
Davies, Kelvin J. A.
Grune, Tilman
Keywords: Oxidative stress
Phosphorylation
Proteasome
RCAN1
Tau protein
Issue Date: 2006
Publisher: © Biochemical Society
Citation: POPPEK, D. ... et al., 2006. Phosphorylation inhibits turnover of the tau protein by the proteasome: Influence of RCAN1 and oxidative stress. Biochemical Journal, 400 (3), pp. 511 - 520.
Abstract: Hyperphosphorylated tau proteins accumulate in the paired helical filaments of neurofibrillary tangles seen in such tauopathies as Alzheimer's disease. In the present paper we show that tau turnover is dependent on degradation by the proteasome (inhibited by MG132) in HT22 neuronal cells. Recombinant human tau was rapidly degraded by the 20 S proteasome in vitro, but tau phosphorylation by GSK3β (glycogen synthase kinase 3β) significantly inhibited proteolysis. Tau phosphorylation was increased in HT22 cells by OA [okadaic acid; which inhibits PP (protein phosphatase) 1 and PP2A] or CsA [cyclosporin A; which inhibits PP2B (calcineurin)], and in PC12 cells by induction of a tet-off dependent RCAN1 transgene (which also inhibits PP2B). Inhibition of PP1/PP2A by OA was the most effective of these treatments, and tau hyperphosphorylation induced by OA almost completely blocked tau degradation in HT22 cells (and in cell lysates to which purified proteasome was added) even though proteasome activity actually increased. Many tauopathies involve both tau hyperphosphorylation and the oxidative stress of chronic inflammation. We tested the effects of both cellular oxidative stress, and direct tau oxidative modification in vitro, on tau proteolysis. In HT22 cells, oxidative stress alone caused no increase in tau phosphorylation, but did subtly change the pattern of tau phosphorylation. Tau was actually less susceptible to direct oxidative modification than most cell proteins, and oxidized tau was degraded no better than untreated tau. The combination of oxidative stress plus OA treatment caused extensive tau phosphorylation and significant inhibition of tau degradation. HT22 cells transfected with tau-CFP (cyan fluorescent protein)/tau-GFP (green fluorescent protein) constructs exhibited significant toxicity following tau hyperphosphorylation and oxidative stress, with loss of fibrillar tau structure throughout the cytoplasm. We suggest that the combination of tau phosphorylation and tau oxidation, which also occurs in tauopathies, may be directly responsible for the accumulation of tau aggregates. © 2006 Biochemical Society.
Description: Closed access
Sponsor: This work was supported by DFG grants, SFB 507 and SFB575 to T. G., and by NIH-NIEHS (National Institutes of Health–National Institutes of Environmental Health Sciences) grant #ES 03598 to K. J. A. D. Special thanks are extended to Professor E. Mandelkow and Professor E. M. Mandelkow for provision of the tau–CFP and htau40 plasmid.
Version: Published
DOI: 10.1042/BJ20060463
URI: https://dspace.lboro.ac.uk/2134/16864
Publisher Link: http://dx.doi.org/10.1042/BJ20060463
ISSN: 0264-6021
Appears in Collections:Closed Access (Mechanical, Electrical and Manufacturing Engineering)

Files associated with this item:

File Description SizeFormat
14- Poppek_2006_Tau.pdfPublished version737.54 kBAdobe PDFView/Open

 

SFX Query

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.