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Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing ?-secretase-independent ERK/CREB signaling.


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? activation had key roles in reducing TFEB expression in PS1-knockout NSCs. Pharmacological inhibition of GSK3? 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.

SUBMITTER: Chong CM 

PROVIDER: S-EPMC6115391 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling.

Chong Cheong-Meng CM   Ke Minjing M   Tan Yuan Y   Huang Zhijian Z   Zhang Ke K   Ai Nana N   Ge Wei W   Qin Dajiang D   Lu Jia-Hong JH   Su Huanxing H  

Cell death & disease 20180829 9


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 he  ...[more]

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