Early and late events induced by polyq-expanded proteins: identification of a common pathogenic property of polyq-expanded proteins. (Articolo in rivista)

Type
Label
  • Early and late events induced by polyq-expanded proteins: identification of a common pathogenic property of polyq-expanded proteins. (Articolo in rivista) (literal)
Anno
  • 2011-01-01T00:00:00+01:00 (literal)
Alternative label
  • Bertoni A, Giuliano P, Galgani M, Rotoli D, Ulianich L, Adornetto A, Santillo MR, Porcellini A, Avvedimento VE. (2011)
    Early and late events induced by polyq-expanded proteins: identification of a common pathogenic property of polyq-expanded proteins.
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Bertoni A, Giuliano P, Galgani M, Rotoli D, Ulianich L, Adornetto A, Santillo MR, Porcellini A, Avvedimento VE. (literal)
Pagina inizio
  • 4727 (literal)
Pagina fine
  • 4741 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 286 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Titolo
  • Early and late events induced by polyq-expanded proteins: identification of a common pathogenic property of polyq-expanded proteins. (literal)
Abstract
  • To find a common pathogenetic trait induced by polyQ-expanded proteins, we have used a conditional expression system in PC12 cells to tune the expression of these proteins and analyze the early and late consequences of their expression. We find that expression for 3 h of a polyQ-expanded protein stimulates cellular reactive oxygen species (ROS) levels and significantly reduces the mitochondrial electrochemical gradient. 24-36 h later, ROS induce DNA damage and activation of the checkpoint kinase, ATM. DNA damage signatures are reversible and persist as long as polyQ-expanded proteins are expressed. Transcription of neural and stress response genes is down-regulated in these cells. Selective inhibition of ATM or histone deacetylase rescues transcription and restores the expression of silenced genes. Eventually, after 1 week, the expression of polyQ-expanded protein also induces endoplasmic reticulum stress. As to the primary mechanism responsible for ROS generation, we find that polyQ-expanded proteins, including native Ataxin-2 and Huntingtin, are selectively sequestered in the lipid raft membrane compartment and interact with gp91, the membrane NADPH-oxidase subunit. Selective inhibition of NADPH oxidase or silencing of H-Ras signaling dissolves the aggregates and eliminates DNA damage. We suggest that targeting of the polyQ-expanded proteins to the lipid rafts activates the resident NADPH oxidase. This triggers a signal linking H-Ras, ROS, and ERK1/2 that maintains and propagates the ROS wave to the nucleus. This mechanism may represent the common pathogenetic signature of all polyQ-expanded proteins independently of the specific context or the function of the native wild type protein. (literal)
Prodotto di
Autore CNR

Incoming links:


Autore CNR di
Prodotto
data.CNR.it