Genome-wide analysis of Saccharomyces cerevisiae identifies cellular processes affecting intracellular aggregation of Alzheimer's amyloid-?42: importance of lipid homeostasis.

ABSTRACT: Amyloid-? (A?)-containing plaques are a major neuropathological feature of Alzheimer's disease (AD). The two major isoforms of A? peptide associated with AD are A?40 and A?42, of which the latter is highly prone to aggregation. Increased presence and aggregation of intracellular A?42 peptides is an early event in AD progression. Improved understanding of cellular processes affecting A?42 aggregation may have implications for development of therapeutic strategies. A?42 fused to green fluorescent protein (A?42-GFP) was expressed in ?4600 mutants of a Saccharomyces cerevisiae genome-wide deletion library to identify proteins and cellular processes affecting intracellular A?42 aggregation by assessing the fluorescence of A?42-GFP. This screening identified 110 mutants exhibiting intense A?42-GFP-associated fluorescence. Four major cellular processes were overrepresented in the data set, including phospholipid homeostasis. Disruption of phosphatidylcholine, phosphatidylserine, and/or phosphatidylethanolamine metabolism had a major effect on intracellular A?42 aggregation and localization. Confocal microscopy indicated that A?42-GFP localization in the phospholipid mutants was juxtaposed to the nucleus, most likely associated with the endoplasmic reticulum (ER)/ER membrane. These data provide a genome-wide indication of cellular processes that affect intracellular A?42-GFP aggregation and may have important implications for understanding cellular mechanisms affecting intracellular A?42 aggregation and AD disease progression.

SUBMITTER: Nair S 

PROVIDER: S-EPMC4116298 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature