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Sphingolipids and inositol phosphates regulate the tau protein phosphorylation status in humanized yeast

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Sphingolipids and inositol phosphates regulate the tau protein phosphorylation status in humanized yeast

dc.contributor.author	Rández Gil, Francisca
dc.contributor.author	Bojunga, Lino
dc.contributor.author	Estruch Ros, Francisco
dc.contributor.author	Winderickx, Joris
dc.contributor.author	Del Poeta, Maurizio
dc.contributor.author	Prieto Alamán, José Antonio
dc.date.accessioned	2021-03-24T15:23:30Z
dc.date.available	2021-03-24T15:23:30Z
dc.date.issued	2020
dc.identifier.citation	Rández-Gil, Francisca Bojunga, Lino Estruch Ros, Francisco Winderickx, Joris Del Poeta, Maurizio Prieto Alamán, José Antonio 2020 Sphingolipids and inositol phosphates regulate the tau protein phosphorylation status in humanized yeast Frontiers In Cell And Developmental Biology 8 592159
dc.identifier.uri	https://hdl.handle.net/10550/78351
dc.description.abstract	Hyperphosphorylation of protein tau is a hallmark of Alzheimer's disease (AD). Changes in energy and lipid metabolism have been correlated with the late onset of this neurological disorder. However, it is uncertain if metabolic dysregulation is a consequence of AD or one of the initiating factors of AD pathophysiology. Also, it is unclear whether variations in lipid metabolism regulate the phosphorylation state of tau. Here, we show that in humanized yeast, tau hyperphosphorylation is stimulated by glucose starvation in coincidence with the downregulation of Pho85, the yeast ortholog of CDK5. Changes in inositol phosphate (IP) signaling, which has a central role in energy metabolism, altered tau phosphorylation. Lack of inositol hexakisphosphate kinases Kcs1 and Vip1 (IP6 and IP7 kinases in mammals) increased tau hyperphosphorylation. Similar effects were found by mutation of IPK2 (inositol polyphosphate multikinase), or PLC1, the yeast phospholipase C gene. These effects may be explained by IP-mediated regulation of Pho85. Indeed, this appeared to be the case for plc1, ipk2, and kcs1. However, the effects of Vip1 on tau phosphorylation were independent of the presence of Pho85, suggesting additional mechanisms. Interestingly, kcs1 and vip1 strains, like pho85, displayed dysregulated sphingolipid (SL) metabolism. Moreover, genetic and pharmacological inhibition of SL biosynthesis stimulated the appearance of hyperphosphorylated forms of tau, while increased flux through the pathway reduced its abundance. Finally, we demonstrated that Sit4, the yeast ortholog of human PP2A protein phosphatase, is a downstream effector of SL signaling in mediating the tau phosphorylation state. Altogether, our results add new knowledge on the molecular effectors involved in tauopathies and identify new targets for pharmacological intervention.
dc.language.iso	eng
dc.relation.ispartof	Frontiers In Cell And Developmental Biology, 2020, vol. 8, p. 592159
dc.subject	Proteïnes
dc.subject	Cèl·lules
dc.title	Sphingolipids and inositol phosphates regulate the tau protein phosphorylation status in humanized yeast
dc.type	journal article	es_ES
dc.date.updated	2021-03-24T15:23:30Z
dc.identifier.doi	10.3389/fcell.2020.592159
dc.identifier.idgrec	141332
dc.rights.accessRights	open access	es_ES