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Molecular Neurobiology

, Volume 55, Issue 5, pp 3841–3855 | Cite as

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

  • Zhenzhen Sun
  • Yujie Xie
  • Yintong Chen
  • Qinghu Yang
  • Zhenzhen Quan
  • Rongji Dai
  • Hong Qing
Article

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.

Keywords

Alzheimer’s disease γ-Secretase Presenilin 1 Co-IP/MS/MS Rab21 Endocytosis 

Abbreviations

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.

Notes

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).

Authors’ 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.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2017_606_MOESM1_ESM.docx (584 kb)
Fig. S1 Effect of Rab21 on APP processing in 2 EB2 cells. (DOCX 583 kb)
12035_2017_606_MOESM2_ESM.docx (1.8 mb)
Fig. S2 The immunostaining of PS1 on cell membrane by three different anti-PS1 antibody. (DOCX 1794 kb)
12035_2017_606_MOESM3_ESM.docx (26 kb)
Table S1 The list of primers for qPCR. (DOCX 26 kb)
12035_2017_606_MOESM4_ESM.docx (36 kb)
Table S2 The list of potential PS1 interacting proteins. (DOCX 35 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.School of Life ScienceBeijing Institute of TechnologyBeijingPeople’s Republic of China

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