Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse

Brain : a Journal of Neurology
Yajing PengLuigi Puglielli

Abstract

The aberrant accumulation of toxic protein aggregates is a key feature of many neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Although they share common pathological features, protein aggregates form in different subcellular locations. Nε-lysine acetylation in the lumen of the endoplasmic reticulum has recently emerged as a new mechanism to regulate the induction of autophagy. The endoplasmic reticulum acetylation machinery includes AT-1/SLC33A1, a membrane transporter that translocates acetyl-CoA from the cytosol into the endoplasmic reticulum lumen, and ATase1 and ATase2, two acetyltransferases that acetylate endoplasmic reticulum cargo proteins. Here, we used a mutant form of α-synuclein to show that inhibition of the endoplasmic reticulum acetylation machinery specifically improves autophagy-mediated disposal of toxic protein aggregates that form within the secretory pathway, but not those that form in the cytosol. Consequently, haploinsufficiency of AT-1/SLC33A1 in the mouse rescued Alzheimer's disease, but not Huntington's disease or amyotrophic lateral sclerosi...Continue Reading

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Citations

Jul 28, 2016·Expert Review of Neurotherapeutics·Anne Poljak, Perminder Singh Sachdev
Oct 12, 2018·Traffic·Dudley W Lamming, Liron Bar-Peled
Jul 28, 2018·Frontiers in Cellular Neuroscience·Anna RonowskaAgnieszka Jankowska-Kulawy
Apr 10, 2020·Frontiers in Neuroscience·Naoki SuzukiMasashi Aoki
Jan 1, 2017·Neurochemical Research·Andrzej SzutowiczJoanna Klimaszewska-Łata
Sep 21, 2017·Frontiers in Neuroscience·Natalia SalvadoresFelipe A Court
Mar 28, 2017·Acta Neuropathologica·Claudia Duran-AniotzClaudio Hetz
Feb 27, 2016·Brain : a Journal of Neurology·Claudia Duran-AniotzClaudio Hetz
Jul 14, 2020·Medicinal Research Reviews·Jiansong FangFeixiong Cheng
Mar 30, 2021·Ageing Research Reviews·Rohan GuptaPravir Kumar

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