@article{bcdb4a9d2cb34a32bad8788d15780a34,
title = "Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons",
abstract = "Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.",
keywords = "cell biology, neuroscience, technical aspects of cell biology",
author = "Takashi Miyata and Daisuke Hagiwara and Yuichi Hodai and Tsutomu Miwata and Yohei Kawaguchi and Junki Kurimoto and Hajime Ozaki and Kazuki Mitsumoto and Hiroshi Takagi and Hidetaka Suga and Tomoko Kobayashi and Mariko Sugiyama and Takeshi Onoue and Yoshihiro Ito and Shintaro Iwama and Ryoichi Banno and Mami Matsumoto and Natsuko Kawakami and Nobuhiko Ohno and Hirotaka Sakamoto and Hiroshi Arima",
note = "Funding Information: The authors thank Dr. Noboru Mizushima (Tokyo University) for providing the GFP-LC3 transgenic mice and Atsuko Imai, Nobuko Hattori (National Institute for Physiological Sciences), and Michiko Yamada for their helpful technical assistance. This work was supported by JSPS KAKENHI Grant Number JP15K19530 (to D.H.); JP16H06280 (to D.H. and H.S.), Grant-in-Aid for Scientific Research on Innovative Areas — Platforms for Advanced Technologies and Research Resources “Advanced Bioimaging Support”; Alexander von Humboldt Foundation Research Fellowship (to D.H.); the Acceleration Program for Intractable Diseases Research utilizing Disease-specific iPS cells (to H.S.) of the Research Center Network for Realization of Regenerative Medicine from the Japanese Agency for Medical Research and Development (AMED); Suzuken Memorial Foundation (to H.A.); and Cooperative Study Programs of National Institute for Physiological Sciences (to H.A. and N.O.). Funding Information: The authors thank Dr. Noboru Mizushima (Tokyo University) for providing the GFP-LC3 transgenic mice and Atsuko Imai, Nobuko Hattori (National Institute for Physiological Sciences), and Michiko Yamada for their helpful technical assistance. This work was supported by JSPS KAKENHI Grant Number JP15K19530 (to D.H.); JP16H06280 (to D.H. and H.S.), Grant-in-Aid for Scientific Research on Innovative Areas ? Platforms for Advanced Technologies and Research Resources ?Advanced Bioimaging Support?; Alexander von Humboldt Foundation Research Fellowship (to D.H.); the Acceleration Program for Intractable Diseases Research utilizing Disease-specific iPS cells (to H.S.) of the Research Center Network for Realization of Regenerative Medicine from the Japanese Agency for Medical Research and Development (AMED); Suzuken Memorial Foundation (to H.A.); and Cooperative Study Programs of National Institute for Physiological Sciences (to H.A. and N.O.). T. Miyata, D.H. H. Sakamoto, N.O. and H.A. designed the studies and wrote the manuscript. T. Miyata, Y.H. T. Miwata, Y.K. J.K. H.O. K.M. H.T. H. Suga, T.K. M.S. T.O. Y.I. S.I. and R.B. performed most of the experiments. N.K. and H. Sakamoto performed the immunoelectron microscopy experiments. M.M. and N.O. performed the SBF-SEM analysis. All authors discussed the results and commented on the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = oct,
day = "23",
doi = "10.1016/j.isci.2020.101648",
language = "English",
volume = "23",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "10",
}
