The Impact of ESCRT on Aβ 1-42 Induced Membrane Lesions in a Yeast Model for Alzheimer's Disease

• Published in: Frontiers in molecular neuroscience Vol. 11; p. 406
• Main Authors: Fruhmann, Gernot, Marchal, Christelle, Vignaud, Hélène, Verduyckt, Mathias, Talarek, Nicolas, De Virgilio, Claudio, Winderickx, Joris, Cullin, Christophe
• Format: Journal Article
• Language: English
• Published: Switzerland 2018
• Subjects: Alzheimer’s disease; Aβ42; ESCRT; Saccharomyces cerevisiae; amyloid beta; yeast; membrane repair
• ISSN: 1662-5099; 1662-5099

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. We used our model to search for genes that modulate this deleterious effect, either by reducing or enhancing Aβ toxicity, based on screening of the yeast knockout collection. This revealed a reduced Aβ toxicity not only in strains hampered in ER-Golgi traffic and mitochondrial functioning but also in strains lacking genes connected to the cell cycle and the DNA replication stress response. On the other hand, increased Aβ toxicity was observed in strains affected in the actin cytoskeleton organization, endocytosis and the formation of multivesicular bodies, including key factors of the ESCRT machinery. Since the latter was shown to be required for the repair of membrane lesions in mammalian systems, we studied this aspect in more detail in our yeast model. Our data demonstrated that Aβ heavily disturbed the plasma membrane integrity in a strain lacking the ESCRT-III accessory factor Bro1, a phenotype that came along with a severe growth defect and enhanced loading of lipid droplets. Thus, it appears that also in yeast ESCRT is required for membrane repair, thereby counteracting one of the deleterious effects induced by the expression of Aβ . Combined, our studies once more validated the use of yeast as a model to investigate fundamental mechanisms underlying the etiology of neurodegenerative disorders.