A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast.
PLoS Genet
; 10(1): e1004010, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24465216
ABSTRACT
Unbiased lipidomic approaches have identified impairments in glycerophosphocholine second messenger metabolism in patients with Alzheimer's disease. Specifically, we have shown that amyloid-ß42 signals the intraneuronal accumulation of PC(O-160/20) which is associated with neurotoxicity. Similar to neuronal cells, intracellular accumulation of PC(O-160/20) is also toxic to Saccharomyces cerevisiae, making yeast an excellent model to decipher the pathological effects of this lipid. We previously reported that phospholipase D, a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding protein, was relocalized in response to PC(O-160/20), suggesting that this neurotoxic lipid may remodel lipid signaling networks. Here we show that PC(O-160/20) regulates the distribution of the PtdIns(4)P 5-kinase Mss4 and its product PtdIns(4,5)P2 leading to the formation of invaginations at the plasma membrane (PM). We further demonstrate that the effects of PC(O-160/20) on the distribution of PM PtdIns(4,5)P2 pools are in part mediated by changes in the biosynthesis of long chain bases (LCBs) and ceramides. A combination of genetic, biochemical and cell imaging approaches revealed that PC(O-160/20) is also a potent inhibitor of signaling through the Target of rampamycin complex 2 (TORC2). Together, these data provide mechanistic insight into how specific disruptions in phosphocholine second messenger metabolism associated with Alzheimer's disease may trigger larger network-wide disruptions in ceramide and phosphoinositide second messenger biosynthesis and signaling which have been previously implicated in disease progression.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosforilcolina
/
Fosfatidilinositol 4,5-Difosfato
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Complexos Multiproteicos
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Serina-Treonina Quinases TOR
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Doença de Alzheimer
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Revista:
PLoS Genet
Assunto da revista:
GENETICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Canadá