The peptidyl prolyl <em>cis/trans</em> isomerase Pin1/Ess1 inhibits phosphorylation and toxicity of tau in a yeast model for Alzheimer's disease

Ann De Vos; Tine Bynens; Joëlle Rosseels; Catherina Coun; Julia Ring; Frank Madeo; Marie-Christine Galas; Joris Winderickx; Vanessa Franssens; Ann De Vos; Tine Bynens; Joëlle Rosseels; Catherina Coun; Julia Ring; Frank Madeo; Marie-Christine Galas; Joris Winderickx; Vanessa Franssens

doi:10.3934/molsci.2015.2.144

AIMS Molecular Science

2015, Volume 2, Issue 2: 144-160. doi: 10.3934/molsci.2015.2.144

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The peptidyl prolyl cis/trans isomerase Pin1/Ess1 inhibits phosphorylation and toxicity of tau in a yeast model for Alzheimer's disease

1.
Functional Biology, Department Biology, KU Leuven, 3001 Heverlee, Belgium;
2.
ADx NeuroSciences NV, Technologiepark 4, 9052 Ghent, Belgium;
3.
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria;
4.
BioTechMed-Graz, 8010 Graz, Austria;
5.
Inserm UMR1172, JPARC, Alzheimer & Tauopathies, 1 rue Michel Polonovski, 59045 Lille, France;
6.
Université de Lille, Faculte de Medecine, 59000 Lille, France;
7.
CHRU, Memory Clinic, 59045 Lille, France

Received: 27 February 2014 Accepted: 23 April 2015 Published: 28 April 2015

Since hyperphosphorylation of protein tau is a crucial event in Alzheimer's disease, additional mechanisms besides the interplay of kinase and phosphatase activities are investigated, such as the effect of the peptidyl prolyl cis/trans isomerase Pin1. This isomerase was shown to bind and isomerize phosphorylated protein tau, thereby restoring the microtubule associated protein function of tau as well as promoting the dephosphorylation of the protein by the trans-dependent phosphatase PP2A. In this study we used models based on Saccharomyces cerevisiae to further elucidate the influence of Pin1 and its yeast ortholog Ess1 on tau phosphorylation and self-assembly. We could demonstrate that in yeast, a lack of Pin1 isomerase activity leads to an increase in phosphorylation of tau at Thr231, comparable to AD brain and consistent with earlier findings in other model organisms. However, we could also distinguish an effect by Pin1 on other residues of tau, i.e. Ser235 and Ser198/199/202. Furthermore, depletion of Pin1 isomerase activity results in reduced growth of the yeast cells, which is enhanced upon expression of tau. This suggests that the accumulation of hyperphosphorylated and aggregation-prone tau causes cytotoxicity in yeast. This study introduces yeast as a valuable model organism to characterize in detail the effect of Pin1 on the biochemical characteristics of protein tau, more specifically its phosphorylation and aggregation.
- Pin1,
- tau,
- yeast,
- phosphorylation,
- Alzheimer's disease
Citation: Ann De Vos, Tine Bynens, Joëlle Rosseels, Catherina Coun, Julia Ring, Frank Madeo, Marie-Christine Galas, Joris Winderickx, Vanessa Franssens. The peptidyl prolyl cis/trans isomerase Pin1/Ess1 inhibits phosphorylation and toxicity of tau in a yeast model for Alzheimer's disease[J]. AIMS Molecular Science, 2015, 2(2): 144-160. doi: 10.3934/molsci.2015.2.144

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Abstract

Since hyperphosphorylation of protein tau is a crucial event in Alzheimer's disease, additional mechanisms besides the interplay of kinase and phosphatase activities are investigated, such as the effect of the peptidyl prolyl cis/trans isomerase Pin1. This isomerase was shown to bind and isomerize phosphorylated protein tau, thereby restoring the microtubule associated protein function of tau as well as promoting the dephosphorylation of the protein by the trans-dependent phosphatase PP2A. In this study we used models based on Saccharomyces cerevisiae to further elucidate the influence of Pin1 and its yeast ortholog Ess1 on tau phosphorylation and self-assembly. We could demonstrate that in yeast, a lack of Pin1 isomerase activity leads to an increase in phosphorylation of tau at Thr231, comparable to AD brain and consistent with earlier findings in other model organisms. However, we could also distinguish an effect by Pin1 on other residues of tau, i.e. Ser235 and Ser198/199/202. Furthermore, depletion of Pin1 isomerase activity results in reduced growth of the yeast cells, which is enhanced upon expression of tau. This suggests that the accumulation of hyperphosphorylated and aggregation-prone tau causes cytotoxicity in yeast. This study introduces yeast as a valuable model organism to characterize in detail the effect of Pin1 on the biochemical characteristics of protein tau, more specifically its phosphorylation and aggregation.

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