The toxicity of an "artificial" amyloid is related to how it interacts with membranes

Area of Science:

• Cell Biology
• Molecular Biology
• Yeast Genetics

Background:

• Amyloid structures are implicated in various diseases, but their toxic molecular species and cellular mechanisms remain poorly understood.
• The precise mechanisms by which amyloid aggregates impair cellular viability are not fully defined and can vary across different diseases.

Purpose of the Study:

• To identify genes that exacerbate the toxicity of a specific amyloid structure (M8) in Saccharomyces cerevisiae.
• To elucidate the cellular mechanisms underlying amyloid-induced toxicity using a yeast model system.

Main Methods:

• Systematic genomic screening in Saccharomyces cerevisiae to identify genes modulating M8 amyloid toxicity.
• Phenotypic analysis of M8-expressing yeast cells, including endocytosis, vacuolar morphology, and salt sensitivity.
• Investigation of the interaction between M8 amyloid and lipids.

Main Results:

• The Vps-C HOPS (homotypic vacuole fusion and protein sorting) complex was identified as a key factor in M8 amyloid toxicity.
• M8 expression induced phenotypes in yeast cells that were identical to those observed in vps mutants.
• Amyloid M8 directly and specifically interacts with lipids, highlighting the role of membrane formation in toxicity.

Conclusions:

• The HOPS complex plays a critical role in mediating amyloid toxicity in yeast.
• Amyloid toxicity may arise from disruptions in membrane dynamics, specifically through a mechanism involving membrane fission.
• These findings propose a novel model for amyloid toxicity centered on membrane fission.