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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2017
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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. |
format | Online Article Text |
id | pubmed-5698481 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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