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Research Article

Bidirectional regulation of Aβ levels by Presenilin 1

Victor Bustos, Maria V. Pulina, Yildiz Kelahmetoglu, Subhash C. Sinha, Fred S. Gorelick, Marc Flajolet, and View ORCID ProfilePaul Greengard
  1. aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
  2. bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
  3. cDepartment of Cell Biology, Yale University School of Medicine, New Haven, CT 06520

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PNAS July 3, 2017 114 (27) 7142-7147; first published May 22, 2017; https://doi.org/10.1073/pnas.1705235114
Victor Bustos
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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  • For correspondence: vbustos@rockefeller.edu greengard@rockefeller.edu
Maria V. Pulina
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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Yildiz Kelahmetoglu
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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Subhash C. Sinha
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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Fred S. Gorelick
bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
cDepartment of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
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Marc Flajolet
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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Paul Greengard
aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
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  • ORCID record for Paul Greengard
  • For correspondence: vbustos@rockefeller.edu greengard@rockefeller.edu
  1. Contributed by Paul Greengard, April 27, 2017 (sent for review March 30, 2017; reviewed by Yue-Ming Li and Sangram S. Sisodia)

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Significance

Alzheimer’s disease is the most common neurodegenerative disorder, affecting more than 5 million people in the United States. Multiple lines of evidence suggest that the accumulation of toxic oligomers and aggregates of β-amyloid (Aβ) peptide are the primary causes of neurodegeneration. Aβ originates from sequential cleavage of the amyloid precursor protein (APP). The APP first cleavage is by β-secretase and yields β-C-terminal fragment (βCTF). In turn, βCTF is cleaved by Presenilin 1 (PS1) to produce Aβ. In this work, we show that PS1, in addition to generating Aβ, can also decrease Aβ levels by directing βCTF degradation through autophagy. This previously unrecognized mechanism of regulation of Aβ by Presenilin 1 could provide an attractive target for potential Alzheimer’s disease therapies.

Abstract

Alzheimer’s disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aβ levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aβ levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aβ peptide and in βCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of βCTF, resulting in its accumulation and increased levels of Aβ peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aβ levels by increasing βCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates βCTF degradation may aid in the development of potential therapies for Alzheimer’s disease.

  • Presenilin 1
  • phosphorylation
  • Alzheimer’s disease
  • Aβ
  • autophagy

Footnotes

  • ↵1To whom correspondence may be addressed. Email: vbustos{at}rockefeller.edu or greengard{at}rockefeller.edu.
  • ↵2Present address: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

  • Author contributions: V.B., M.V.P., F.S.G., M.F., and P.G. designed research; V.B., M.V.P., and Y.K. performed research; V.B., M.V.P., and S.C.S. contributed new reagents/analytic tools; V.B., M.V.P., Y.K., F.S.G., M.F., and P.G. analyzed data; and V.B., M.V.P., F.S.G., M.F., and P.G. wrote the paper.

  • Reviewers: Y.-M.L., Memorial Sloan–Kettering Cancer Center; and S.S.S., The University of Chicago.

  • The authors declare no conflict of interest.

  • See Commentary on page 6885.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1705235114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Antiamyloidogenic function of Presenilin 1
Victor Bustos, Maria V. Pulina, Yildiz Kelahmetoglu, Subhash C. Sinha, Fred S. Gorelick, Marc Flajolet, Paul Greengard
Proceedings of the National Academy of Sciences Jul 2017, 114 (27) 7142-7147; DOI: 10.1073/pnas.1705235114

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Antiamyloidogenic function of Presenilin 1
Victor Bustos, Maria V. Pulina, Yildiz Kelahmetoglu, Subhash C. Sinha, Fred S. Gorelick, Marc Flajolet, Paul Greengard
Proceedings of the National Academy of Sciences Jul 2017, 114 (27) 7142-7147; DOI: 10.1073/pnas.1705235114
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  • Versatility of Presenilin 1
    - Jun 23, 2017

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  • PS1 increases autophagosome–lysosome fusion
    - May 22, 2017
Proceedings of the National Academy of Sciences: 114 (27)
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