RRC ID 56218
著者 Sarasija S, Laboy JT, Ashkavand Z, Bonner J, Tang Y, Norman KR.
タイトル Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans.
ジャーナル Elife
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.
巻・号 7
公開日 2018-7-10
DOI 10.7554/eLife.33052
PII 33052
PMID 29989545
PMC PMC6075864
MeSH Alzheimer Disease / genetics Alzheimer Disease / metabolism Alzheimer Disease / pathology Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Calcium / metabolism* Cells, Cultured Endoplasmic Reticulum / metabolism Fibroblasts / metabolism Fibroblasts / pathology Gene Expression Regulation Homeostasis Humans Mechanotransduction, Cellular Membrane Proteins / genetics* Membrane Proteins / metabolism Mitochondria / metabolism Mitochondria / pathology* Mutation* Neurodegenerative Diseases / genetics Neurodegenerative Diseases / metabolism Neurodegenerative Diseases / pathology* Oxidative Stress Presenilin-1 / genetics Presenilin-1 / metabolism Reactive Oxygen Species / metabolism Signal Transduction Skin / metabolism Skin / pathology
IF 7.551
引用数 16
リソース情報
線虫 tm6026