Development of a new model for the study of Tauopathies

Two of the main hallmarks in many neurodegenerative diseases called tauopathies are hyperfosforylation and aggregation of protein Tau. A lot of research on the processes involved in tau biology has been done in a well known yeast model for the study of Tau biology, namely the Saccharomyces cerevisiae model. In order to study toxicity of Tau in yeast cells in parallel with the hyperfosforylation and aggregation, we have developed a new Schizosaccharomyces pombe yeast model. On this poster we show some crucial results that were obtained in this human tau-expressing yeast model that can pinpoint the potential of this model for future studies for the modulators of Tau toxicity and the cellular processes involved in Tau biology.status: publishe

Yeast as a Model for Alzheimer's Disease: Latest Studies and Advanced Strategies

The yeast Saccharomyces cerevisiae, a unicellular eukaryotic model, has enabled major breakthroughs in our understanding of a plethora of cellular and molecular processes. Today, a 're-invention' of its use in fundamental and applied research is paving the way for a better understanding of the mechanisms causing neurodegeneration. The increasing emergence of neurodegenerative disorders is becoming more and more problematic in our ageing society. Most prevalent is Alzheimer's disease (AD), affecting more than 35 million people worldwide (Abbott, Nature 475, S2-S4, 2011) and causing an enormous burden on a personal and communal level. The disease is characterized by two major pathological hallmarks: extracellular amyloid plaques consisting mainly of deposits of amyloid β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs), consisting mainly of aggregates of hyperphosphorylated tau protein. Despite the huge importance of thoroughly understanding the underlying molecular mechanisms of neurodegeneration, progress has been slow. However, multiple complementary research methods are proving their value, particularly with the work done with S. cerevisiae, which combines well-established, fast genetic and molecular techniques with the ability to faithfully capture key molecular aspects of neurodegeneration. In this review chapter, we focus on the considerable progress made using S. cerevisiae as a model system for Alzheimer's disease.status: publishe

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

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

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

status: publishe