Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans

  1. Shaarika Sarasija
  2. Jocelyn T Laboy
  3. Zahra Ashkavand
  4. Jennifer Bonner
  5. Yi Tang
  6. Kenneth R Norman  Is a corresponding author
  1. Albany Medical College, United States
  2. Skidmore College, United States

Abstract

Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the C. elegans gene encoding a PSEN homolog, sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In sel-12 mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca2+ signaling leads to an increase in mitochondrial Ca2+ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca2+ release, mitochondrial Ca2+ uptake or mitochondrial superoxides in sel-12 mutants, we demonstrate rescue of the mitochondrial metabolic defects and prevent neurodegeneration. These data suggest that mutations in PSEN alter mitochondrial metabolic function via ER to mitochondrial Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases.

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Source data files have be proved for all figures.

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Author details

  1. Shaarika Sarasija

    Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3610-2178
  2. Jocelyn T Laboy

    Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zahra Ashkavand

    Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jennifer Bonner

    Department of Biology, Skidmore College, Saratoga Springs, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yi Tang

    Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kenneth R Norman

    Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States
    For correspondence
    normank@mail.amc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0773-9073

Funding

National Institute of General Medical Sciences (GM088213)

  • Yi Tang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew Dillin, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: October 24, 2017
  2. Accepted: July 9, 2018
  3. Accepted Manuscript published: July 10, 2018 (version 1)
  4. Version of Record published: August 3, 2018 (version 2)

Copyright

© 2018, Sarasija et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shaarika Sarasija
  2. Jocelyn T Laboy
  3. Zahra Ashkavand
  4. Jennifer Bonner
  5. Yi Tang
  6. Kenneth R Norman
(2018)
Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans
eLife 7:e33052.
https://doi.org/10.7554/eLife.33052

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