title: Autophagy impairment stimulates PS1 expression and gamma-secretase activity.
abstract: Gamma-secretase plays an important role in the development of Alzheimer disease (AD). Gamma-secretase activity is enriched in autophagic vacuoles and it augments amyloid-beta (Abeta) synthesis. Autophagy-lysosomal dysfunction has been implicated in AD, but whether gamma-secretase activity is affected by autophagy remains unclear. Here we report that gamma-secretase activity is enhanced in basal autophagy-disturbed cells through the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) kinase, general control nonderepressible 2 (GCN2). Presenilin-1 (PS1) expression was increased even in the presence of nutrients in autophagy-related 5 knockdown (Atg5KD) human embryonic kidney (HE K293) cells expressing a short hairpin RNA as well as in chloroquine-treated HE K293 cells. However, PS1 expression induction was prevented in GCN2KD and ATF4KD cells. Furthermore, Atg5KD cells showed an increase in Abeta production and Notch1 cleavage. These were reduced by an autophagy inducer, resveratrol. Thus, we conclude that the autophagy-lysosomal system regulates gamma-secretase activity through GCN2.
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohta
authors.forename: Akihito
authors.initials: A
authors.lastname: Mizuno
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueda
authors.forename: Shimo
authors.initials: S
authors.lastname: Li
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hida
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Hayakawa-Yano
authors.forename: Masanori
authors.initials: M
authors.lastname: Itoh
authors.forename: Eri
authors.initials: E
authors.lastname: Ohta
authors.forename: Masuko
authors.initials: M
authors.lastname: Kobori
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; C502778:ATG5 protein, human; D016229:Amyloid beta-Peptides; D000071187:Autophagy-Related Protein 5; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D053764:Presenilin-1; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases