The Impact of ESCRT on Aβ Induced Membrane Lesions in a Yeast Model for Alzheimer's Disease.

Aβ metabolism plays a pivotal role in Alzheimer's disease. Here, we used a yeast model to monitor Aβ toxicity when entering the secretory pathway and demonstrate that processing in, and exit from the endoplasmic reticulum (ER) is required to unleash the full Aβ toxic potential. Consistent with previously reported data, our data suggests that Aβ interacts with mitochondria, thereby enhancing formation of reactive oxygen species and eventually leading to cell demise.

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.

Background: The most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors.

Synthetic toxic Aβ oligomers can assemble in different morphologies.

Background: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aβ peptides. Aβ toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aβ in a eukaryotic cellular system and selected synthetic variants on their sole toxicity.

Gene duplication can impart fragility, not robustness, in the yeast protein interaction network.

The maintenance of duplicated genes is thought to protect cells from genetic perturbations, but the molecular basis of this robustness is largely unknown. By measuring the interaction of yeast proteins with their partners in wild-type cells and in cells lacking a paralog, we found that 22 out of 56 paralog pairs compensate for the lost interactions. An equivalent number of pairs exhibit the opposite behavior and require each other's presence for maintaining their interactions.

Multi-scale perturbations of protein interactomes reveal their mechanisms of regulation, robustness and insights into genotype-phenotype maps.

Cellular architectures and signaling machineries are organized through protein-protein interactions (PPIs). High-throughput methods to study PPIs in yeast have opened a new perspective on the organization of the cell by allowing the study of whole protein interactomes. Recent investigations have moved from the description of this organization to the analysis of its dynamics by experimenting how protein interaction networks (PINs) are rewired in response to perturbations.

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.

Interaction of Aβ(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage.

The toxicity of amyloids, as Aβ(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Aβ(1-42) peptides and variants (L34T, mG37C) produced in E.

The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition.

Hypoxia inducible factor 1α (HIF-1α) is a master regulator of tumor angiogenesis being one of the major targets for cancer therapy. Previous studies have shown that Histone Deacetylase Inhibitors (HDACi) block tumor angiogenesis through the inhibition of HIF-1α expression. As such, Vorinostat (Suberoylanilide Hydroxamic Acid/SAHA) and Romidepsin, two HDACis, were recently approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma.

A structure-toxicity study of Aß42 reveals a new anti-parallel aggregation pathway.

Amyloid beta (Aβ) peptides produced by APP cleavage are central to the pathology of Alzheimer's disease. Despite widespread interest in this issue, the relationship between the auto-assembly and toxicity of these peptides remains controversial. One intriguing feature stems from their capacity to form anti-parallel ß-sheet oligomeric intermediates that can be converted into a parallel topology to allow the formation of protofibrillar and fibrillar Aβ.

A yeast model for amyloid-β aggregation exemplifies the role of membrane trafficking and PICALM in cytotoxicity.

Alzheimer's disease is the most common neurodegenerative disease, associated with aggregation of amyloid-β (Aβ) peptides. The exact mechanism of neuronal cell dysfunction in Alzheimer's disease is poorly understood and numerous models have been used to decipher the mechanisms leading to cellular death. Yeast cells might be a good model to understand the intracellular toxicity triggered by Aβ peptides.