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


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.

SUBMITTER: Sarasija S 

PROVIDER: S-EPMC6075864 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Presenilin mutations deregulate mitochondrial Ca<sup>2+</sup> homeostasis and metabolic activity causing neurodegeneration in <i>Caenorhabditis elegans</i>.

Sarasija Shaarika S   Laboy Jocelyn T JT   Ashkavand Zahra Z   Bonner Jennifer J   Tang Yi Y   Norman Kenneth R KR  

eLife 20180710


Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (<i>PSEN1</i> and <i>PSEN2</i>) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the <i>C. elegans</i> gene encoding a PSEN homolog, <i>sel-12</i> result in mitochondrial metabolic defects that promote neurodegeneration as a res  ...[more]

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