Title: Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease
Legend: Figure. ATase inhibition rescues the CMT-like phenotype of Pmp22Tr-J mice. The inhibition of the ATases in the lumen of the endoplasmic reticulum (ER) stimulates the induction of ER-specific autophagy (reticulophagy) and the removal of toxic protein aggregates that form within the lumen of the organelle. Here, Fernandez-Fuente et al. used three mouse models of Charcot-Marie-Tooth disease, Pmp22Tr-J, C3-PMP22, and Mpzttrr, to study spatial and translational selectivity of ATase inhibitors. The results show that ATase inhibition selectively targets misfolding/pro-aggregating events occurring in the lumen of the ER. Therefore, they establish the ATases as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the ER/secretory pathway.
Citation: Fernandez-Fuente, G., Farrugia, M. A., Peng, Y., Schneider, A., Svaren, J., & Puglielli, L. (2024). Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease. Brain communications, 6(4), fcae232. https://doi.org/10.1093/braincomms/fcae232
Abstract: The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.
Investigator: Luigi Puglielli, MD, PhD
About the Lab: The Puglielli Lab’s research interests focus on molecular mechanisms of neurodevelopment and neurodegeneration. The laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models. In 2007 the lab reported that nascent proteins could undergo Nε-lysine acetylation in the lumen of the endoplasmic reticulum (ER). This discovery resulted in the identification of a previously unknown biochemical machinery that impacts on the biology of the ER.