Autophagy impairment stimulates PS1 expression and gamma-secretase activity.
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.
Ohta
Kazunori
K
Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Mizuno
Akihito
A
Ueda
Masashi
M
Li
Shimo
S
Suzuki
Yoshihiro
Y
Hida
Yoko
Y
Hayakawa-Yano
Yoshika
Y
Itoh
Masanori
M
Ohta
Eri
E
Kobori
Masuko
M
Nakagawa
Toshiyuki
T
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*
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