Functional Links Between A beta Toxicity, Endocytic Trafficking, and Alzheimer's Disease Risk Factors in Yeast

Abstract

A beta (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled A beta toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to A beta was previously unknown. The factors identified in yeast modified A beta toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, A beta impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between A beta, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

Description
Keywords
GENOME-WIDE ASSOCIATION, ALPHA-SYNUCLEIN, SACCHAROMYCES-CEREVISIAE, ENDOPLASMIC-RETICULUM, IDENTIFIES VARIANTS, COMMON VARIANTS, PEPTIDE, OLIGOMERS, MEMBRANE, CELLS, Multidisciplinary Sciences
Citation
Treusch, S., Hamamichi, S., Goodman, J. L., Matlack, K. E. S., Chung, C. Y., Baru, V., Shulman, J. M., Parrado, A., Bevis, B. J., Valastyan, J. S., Han, H., Lindhagen-Persson, M., Reiman, E. M., Evans, D. A., Bennett, D. A., Olofsson, A., DeJager, P. L., Tanzi, R. E., Caldwell, K. A., … Lindquist, S. (2011). Functional Links Between Aβ Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast. In Science (Vol. 334, Issue 6060, pp. 1241–1245). American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/science.1213210