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Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling
Cheong-Meng Chong1; Minjing Ke1; Yuan Tan1; Zhijian Huang1; Ke Zhang1; Nana Ai2; Wei Ge2; Dajiang Qin3; Jia-Hong Lu1; Huanxing Su1
2018-08-29
Source PublicationCELL DEATH & DISEASE
ISSN2041-4889
Volume9Pages:1-13
Abstract

Autophagy impairment is commonly implicated in the pathological characteristic of Alzheimer's disease (AD). Presenilin 1 (PS1) expression in human brain gradually decreases with age and its mutations account for the most common cases of early-onset familial Alzheimer's disease (FAD). The dominant autophagy phenotypes occur in PS1-knockout and PS1 mutant neurons; it is still unknown whether PS1 deficiency causes serious autophagy impairment in neural stem cells (NSCs). Herein, we generated the heterozygote and homozygote of PS1 knockout in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9-based gene editing and differentiated them into human NSCs. In these human PS1-deficient NSCs, reduced autophagosome formation and downregulated expression of autophagy-lysosome pathway (ALP)-related mRNAs, as well as proteins were observed. Mechanistically, ERK/CREB inhibition and GSK3 beta activation had key roles in reducing TFEB expression in PS1-knockout NSCs. Pharmacological inhibition of GSK3 beta upregulated the expression of TFEB and ALP-related proteins in PS1-knockout NSCs, whereas this effect could be blocked by CREB inhibition. These findings demonstrate that PS1 deficiency causes autophagy suppression in human NSCs via downregulating ERK/CREB signaling.

DOIhttp://doi.org/10.1038/s41419-018-0945-7
Indexed BySCI
Language英语
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000443088000015
PublisherNATURE PUBLISHING GROUP
The Source to ArticleWOS
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorDajiang Qin; Jia-Hong Lu; Huanxing Su
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macao, China
3.CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cheong-Meng Chong,Minjing Ke,Yuan Tan,et al. Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling[J]. CELL DEATH & DISEASE,2018,9:1-13.
APA Cheong-Meng Chong.,Minjing Ke.,Yuan Tan.,Zhijian Huang.,Ke Zhang.,...&Huanxing Su.(2018).Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling.CELL DEATH & DISEASE,9,1-13.
MLA Cheong-Meng Chong,et al."Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling".CELL DEATH & DISEASE 9(2018):1-13.
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