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Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity.

Vincenzo Sorrentino | Mario Romani | Laurent Mouchiroud | John S Beck | Hongbo Zhang | Davide D'Amico | Norman Moullan | Francesca Potenza | Adrien W Schmid | Solène Rietsch | Scott E Counts | Johan Auwerx
Nature | 2017

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

Pubmed ID: 29211722

Research resources used in this publication

None found

Antibodies used in this publication

None found

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: P30 AG053760
  • Agency: NIH HHS, United States
    Id: P40 OD010440
  • Agency: NIA NIH HHS, United States
    Id: R01 AG043930
  • Agency: NIA NIH HHS, United States
    Id: P01 AG014449
  • Agency: NIA NIH HHS, United States
    Id: R21 AG053581

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