GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway

Hyrskyluoto, AliseUniv Helsinki, Inst Biomed Biochem, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki, Minerva Med Res Inst, FIN-00290 Helsinki, Finland. (author)

Increased protein aggregation and altered cell signaling accompany many neurodegenerative diseases including Huntington's disease (HD). Cell stress is counterbalanced by signals mediating cell repair but the identity of these are not fully understood. We show here that the mammalian target of rapamycin (mTOR) pathway is inhibited and cytoprotective autophagy is activated in neuronal PC6.3 cells at 24 h after expression of mutant huntingtin proteins. Tuberous sclerosis complex (TSC) 1/2 interacted with growth arrest and DNA damage protein 34 (GADD34), which caused TSC2 dephosphorylation and induction of autophagy in mutant huntingtin expressing cells. However, GADD34 and autophagy decreased at later time points, after 48 h of transfection with the concomitant increase in mTOR activity. Overexpression of GADD34 counteracted these effects and increased cytoprotective autophagy and cell survival. These results show that GADD34 plays an important role in cell protection in mutant huntingtin expressing cells. Modulation of GADD34 and the TSC pathway may prove useful in counteracting cell degeneration accompanying HD and other neurodegenerative diseases. (C) 2011 Elsevier Inc. All rights reserved.

Reijonen, SamiUniv Helsinki, Dept Vet Biosci, Unit Biochem & Cell Biol, FIN-00014 Helsinki, Finland. (author)
Kivinen, JennyUniv Helsinki, Inst Biomed Biochem, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki, Minerva Med Res Inst, FIN-00290 Helsinki, Finland. (author)
Lindholm, DanUniv Helsinki, Inst Biomed Biochem, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki, Minerva Med Res Inst, FIN-00290 Helsinki, Finland. (author)
Korhonen, LauraLinköpings universitet,Univ Helsinki, Inst Biomed Biochem, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki, Minerva Med Res Inst, FIN-00290 Helsinki, Finland.;Univ Helsinki, Div Child Psychiat, Cent Hosp, FIN-00029 Helsinki, Finland. (author)
Univ Helsinki, Inst Biomed Biochem, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki, Minerva Med Res Inst, FIN-00290 Helsinki, Finland.Univ Helsinki, Dept Vet Biosci, Unit Biochem & Cell Biol, FIN-00014 Helsinki, Finland. (creator_code:org_t)

By the author/editor: Hyrskyluoto, Ali ...; Reijonen, Sami; Kivinen, Jenny; Lindholm, Dan; Korhonen, Laura

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