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- Title
ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.
- Authors
Murie, Maeghan; Peng, Yajing; Rigby, Michael J.; Dieterich, Inca A.; Farrugia, Mark A.; Endresen, Andreas; Bhattacharyya, Anita; Puglielli, Luigi
- Abstract
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. Murie et al use in silico docking and affinity binding to identify ATase1 and ATase2 specific inhibitors, and AT1 sTg and APP/PS1 mice to test their translational potential. Their study suggests that ATase-targeting approaches might offer a translational pathway for many ageassociated proteopathies affecting the ER/secretory pathway
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03118-0