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ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.

Maeghan MurieYajing PengMichael J RigbyInca A DieterichMark A FarrugiaAndreas EndresenAnita BhattacharyyaLuigi Puglielli
Published in: Communications biology (2022)
Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer's disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.
Keyphrases
  • endoplasmic reticulum
  • estrogen receptor
  • mouse model
  • breast cancer cells
  • cell death
  • signaling pathway
  • oxidative stress
  • endoplasmic reticulum stress
  • type diabetes
  • cognitive decline
  • skeletal muscle
  • adipose tissue