Details

Autor(en) / Beteiligte

• Sorrentino, Vincenzo
• Romani, Mario
• Mouchiroud, Laurent
• Beck, John S.
• Zhang, Hongbo
• D’Amico, Davide
• Moullan, Norman
• Potenza, Francesca
• Schmid, Adrien W.
• Rietsch, Solène
• Counts, Scott E.
• Auwerx, Johan

Titel

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Ist Teil von

• Nature (London), 2017-12, Vol.552 (7684), p.187-193

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Amyloid-β peptide proteopathies disrupt mitochondria, and restoring mitochondrial proteostasis reduces protein aggregation in animal models of amyloid-β disease. Mitochondrial proteostasis lowers amyloid-β levels Proteotoxic stress—the accumulation of toxic misfolded proteins in cells—is associated with mitochondrial dysfunction. Johan Auwerx and colleagues now identify mitochondrial proteostasis as a key mechanism in the response to proteotoxic stress caused by the accumulation of amyloid-β. Amyloid-β accumulation induces both the mitochondrial stress response and mitophagy in a manner that is conserved from worms to humans. Boosting this response is beneficial in worms, mammalian cells in culture and a mouse model of Alzheimer's disease. These data suggest that enhancing mitochondrial proteostasis may be useful in managing amyloid-β proteopathies in humans.