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G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca2+ Accumulation

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Abstract

Early-onset familial Alzheimer’s disease (AD) is most commonly associated with the mutations in presenilin-1 (PS1). PS1 is the catalytic component of the γ-secretase complex, which cleaves amyloid precursor protein to produce amyloid-β (Aβ), the major cause of AD. Presenilin enhancer 2 (Pen2) is critical for activating γ-secretase and exporting PS1 from endoplasmic reticulum (ER). Among all the familial AD-linked PS1 mutations, mutations at the G206 amino acid are the most adjacent position to the Pen2 binding site. Here, we characterized the effect of a familial AD-linked PS1 G206D mutation on the PS1-Pen2 interaction and the accompanied alteration in γ-secretase-dependent and -independent functions. We found that the G206D mutation reduced PS1-Pen2 interaction, but did not abolish γ-secretase formation and PS1 endoproteolysis. For γ-secretase-dependent function, the G206D mutation increased Aβ42 production but not Notch cleavage. For γ-secretase-independent function, this mutation disrupted the ER calcium homeostasis but not lysosomal calcium homeostasis and autophagosome maturation. Impaired ER calcium homeostasis may due to the reduced mutant PS1 level in the ER. Although this mutation did not alter the cell survival under stress, both increased Aβ42 ratio and disturbed ER calcium regulation could be the mechanisms underlying the pathogenesis of the familial AD-linked PS1 G206D mutation.

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Acknowledgments

We thank Dr. De Strooper for providing PS-null MEF, Dr. Yung-Feng Liao for providing HA-Aph1, Flag-Pen2, wild-type human PS1, and DsRed-GFP-LC3-expressing plasmids, Dr. Liang-Tung Yang for providing NotchΔmyc- and V/LΔmyc-expressing plasmids, and Dr. Rey-Huei Chen for EGFP-Sec61β and EGFP-Rab5 expressing plasmids. This work is supported by Taiwan Ministry of Science and Technology grant (NSC 102-2320-B-010-021-MY2), National Health Research Institute (NHRI-EX98-9816NC), Cheng Hsin General Hospital (102F218C05), Yen Tjing Ling Medical Foundation (CI-102-4), Taipei Veterans General Hospital grant (V103E4-002), and Taiwan Ministry of Education Aim for Top University Grant.

Conflict of Interest

The authors declare that they have no competing interests.

Author Contributions

I.H.C. designed research and analyzed data; W.T.C., Y.F.H., Y.J.H., C.C.L., and Y.T.L. performed research and analyzed data; Y.C.L. and C.C.L. helped with Ca2+ imaging analysis; and W.T.C. and I.H.C. wrote the paper.

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Authors and Affiliations

  1. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan

    Wei-Ting Chen

  2. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

    Wei-Ting Chen, Yi-Fang Hsieh, Che-Ching Lin, Yen-Tung Lin & Irene Han-Juo Cheng

  3. Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan

    Wei-Ting Chen

  4. Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

    Yan-Jing Huang

  5. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan

    Yu-Chao Liu & Cheng-Chang Lien

  6. Brain Research Center, National Yang-Ming University, Taipei, Taiwan

    Cheng-Chang Lien & Irene Han-Juo Cheng

  7. Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan

    Irene Han-Juo Cheng

  8. Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Irene Han-Juo Cheng

  9. Institute of Brain Science, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan

    Irene Han-Juo Cheng

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  1. Wei-Ting Chen
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Correspondence to Irene Han-Juo Cheng.

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Chen, WT., Hsieh, YF., Huang, YJ. et al. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca2+ Accumulation. Mol Neurobiol 52, 1835–1849 (2015). https://doi.org/10.1007/s12035-014-8969-1

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