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L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease

Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (−/−). Under serum-starved conditions, NPC (−/−) cells m...

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Autores principales: Yanagisawa, Hiroko, Ishii, Tomohiro, Endo, Kentaro, Kawakami, Emiko, Nagao, Kazuaki, Miyashita, Toshiyuki, Akiyama, Keiko, Watabe, Kazuhiko, Komatsu, Masaaki, Yamamoto, Daisuke, Eto, Yoshikatsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698481/
https://www.ncbi.nlm.nih.gov/pubmed/29162837
http://dx.doi.org/10.1038/s41598-017-15305-9
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author Yanagisawa, Hiroko
Ishii, Tomohiro
Endo, Kentaro
Kawakami, Emiko
Nagao, Kazuaki
Miyashita, Toshiyuki
Akiyama, Keiko
Watabe, Kazuhiko
Komatsu, Masaaki
Yamamoto, Daisuke
Eto, Yoshikatsu
author_facet Yanagisawa, Hiroko
Ishii, Tomohiro
Endo, Kentaro
Kawakami, Emiko
Nagao, Kazuaki
Miyashita, Toshiyuki
Akiyama, Keiko
Watabe, Kazuhiko
Komatsu, Masaaki
Yamamoto, Daisuke
Eto, Yoshikatsu
author_sort Yanagisawa, Hiroko
collection PubMed
description Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (−/−). Under serum-starved conditions, NPC (−/−) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (−/−) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (−/−) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (−/−) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L-leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1.
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spelling pubmed-56984812017-11-30 L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease Yanagisawa, Hiroko Ishii, Tomohiro Endo, Kentaro Kawakami, Emiko Nagao, Kazuaki Miyashita, Toshiyuki Akiyama, Keiko Watabe, Kazuhiko Komatsu, Masaaki Yamamoto, Daisuke Eto, Yoshikatsu Sci Rep Article Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (−/−). Under serum-starved conditions, NPC (−/−) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (−/−) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (−/−) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (−/−) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L-leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1. Nature Publishing Group UK 2017-11-21 /pmc/articles/PMC5698481/ /pubmed/29162837 http://dx.doi.org/10.1038/s41598-017-15305-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yanagisawa, Hiroko
Ishii, Tomohiro
Endo, Kentaro
Kawakami, Emiko
Nagao, Kazuaki
Miyashita, Toshiyuki
Akiyama, Keiko
Watabe, Kazuhiko
Komatsu, Masaaki
Yamamoto, Daisuke
Eto, Yoshikatsu
L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title_full L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title_fullStr L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title_full_unstemmed L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title_short L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease
title_sort l-leucine and spns1 coordinately ameliorate dysfunction of autophagy in mouse and human niemann-pick type c disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698481/
https://www.ncbi.nlm.nih.gov/pubmed/29162837
http://dx.doi.org/10.1038/s41598-017-15305-9
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