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Rab21, a Novel PS1 Interactor, Regulates γ-Secretase Activity via PS1 Subcellular Distribution

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Abstract

γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer’s disease (AD) pathology. Recently, γ-secretase-associating proteins showed promising role in specifically modulating APP processing while sparing Notch signaling; however, the underlying mechanism is still unclear. A co-immunoprecipitation (Co-IP) coupled with mass spectrometry proteomic assay for Presenilin1 (PS1, the catalytic subunit of γ-secretase) was firstly conducted to find more γ-secretase-associating proteins. Gene ontology analysis of these results identified Rab21 as a potential PS1 interacting protein, and the interaction between them was validated by reciprocal Co-IP and immunofluorescence assay. Then, molecular and biochemical methods were used to investigate the effect of Rab21 on APP processing. Results showed that overexpression of Rab21 enhanced Aβ generation, while silencing of Rab21 reduced the accumulation of Aβ, which resulted due to change in γ-secretase activity rather than α- or β-secretase. Finally, we demonstrated that Rab21 had no effect on γ-secretase complex synthesis or metabolism but enhanced PS1 endocytosis and translocation to late endosome/lysosome. In conclusion, we identified a novel γ-secretase-associating protein Rab21 and illustrate that Rab21 promotes γ-secretase internalization and translocation to late endosome/lysosome. Moreover, silencing of Rab21 decreases the γ-secretase activity in APP processing thus production of Aβ. All these results open new gateways towards the understanding of γ-secretase-associating proteins in APP processing and make inhibition of Rab21 a promising strategy for AD therapy.

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Abbreviations

Aβ:

β-amyloid

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

APP-CTF:

C-Terminal Fragment of APP

Aph1:

anterior pharynx-defective 1

BACE1:

β-site APP cleaving enzyme 1

Co-IP:

co-immunoprecipitation

CALM/PICALM:

phosphatidylinositol binding clathrin assembly protein

EE:

Early endosome

EEA1:

Early endosome antigen1

FAD:

familial Alzheimer’s disease

PS1:

Presenilin1

PS1-FL:

Full length Presenilin1

PS1-CT:

C terminus of Presenilin1

PS1-NT:

N terminus of Presenilin1

PEN2:

Presenilin enhancer-2

NCT:

Nicastrin

LAMP1:

Lysosome-associated membrane protein1

LE:

Late endosome

shRNA:

short hairpin RNA

shRab21:

short hairpin RNA of Rab21

TGN:

trans Golgi network.

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Acknowledgements

We thank Talal Jamil Qazi and Kefu Liu for their help in manuscript drafting. This study was supported by the National Natural Science Foundation of China (81671268), the National Key Scientific Instrument and Equipment Development Project (2013YQ03059514), China Postdoctoral Science Foundation funded project (2016M600931), and a grant from Beijing municipal science and technology commission (Z161100002616020).

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Authors and Affiliations

  1. School of Life Science, Beijing Institute of Technology, Beijing, 100081, People’s Republic of China

    Zhenzhen Sun, Yujie Xie, Yintong Chen, Qinghu Yang, Zhenzhen Quan, Rongji Dai & Hong Qing

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  1. Zhenzhen Sun
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  2. Yujie Xie
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  3. Yintong Chen
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  4. Qinghu Yang
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  7. Hong Qing
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Contributions

Zhenzhen Sun and Hong Qing designed the study. Zhenzhen Sun, Yujie Xie, and Yintong Chen performed the experiment. Zhenzhen Sun analyzed the data and wrote the manuscript. Qinghu Yang and Zhenzhen Quan helped to revise the manuscript. Dai Rongji provided assistance in data analysis.

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Correspondence to Hong Qing.

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Electronic supplementary material

Fig. S1

Effect of Rab21 on APP processing in 2 EB2 cells. (DOCX 583 kb)

Fig. S2

The immunostaining of PS1 on cell membrane by three different anti-PS1 antibody. (DOCX 1794 kb)

Table S1

The list of primers for qPCR. (DOCX 26 kb)

Table S2

The list of potential PS1 interacting proteins. (DOCX 35 kb)

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Sun, Z., Xie, Y., Chen, Y. et al. Rab21, a Novel PS1 Interactor, Regulates γ-Secretase Activity via PS1 Subcellular Distribution. Mol Neurobiol 55, 3841–3855 (2018). https://doi.org/10.1007/s12035-017-0606-3

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