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.
Highlights
Tau protein is a microtubule associated protein (MAP), abundantly expressed in neurons of the central nervous system where it modulates the stability of axonal microtubules (MT)
We observed an enhanced generation of inclusions in the ess1ts strain. This was not associated with higher levels of sarkosyl insoluble tau (SinT), which is considered to represent mature aggregates of the protein. These results suggest that the inclusions in the Pin1 yeast model are rather accumulations of monomeric/oligomeric tau or possibly protofibrils
Depletion of Ess1 leads to slow growth that can be restored by expression of human Pin1
Summary
Tau protein is a microtubule associated protein (MAP), abundantly expressed in neurons of the central nervous system where it modulates the stability of axonal microtubules (MT). Binding to MT is dynamically controlled by reversible phosphorylation, as a result of the activities of different kinases and phosphatases. Ser/Thr-Pro motifs in proteins can exist in two distinct conformations i.e. cis and trans, which slowly interconvert. Phosphorylation of protein tau on Thr231-Pro232 for example slows down the conversion from the cis to the trans state, making this tau residue a less favorable target for the trans-dependent phosphatase PP2A [3]. Pin recognizes phospho-Ser/Thr-Pro motifs in proteins, like the AD-related phosphorylated proteins tau and APP [5,6], and facilitates the cis/trans interconversion of the proline amide bond [3,4,7]. Pin1−/− mice display an age-dependent full-blown tau pathology [9] whereas a decreased Pin expression/activity is reported in case of AD [4,9,10,11]
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