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Under serum-starved conditions, NPC (\u2212\/\u2212) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (\u2212\/\u2212) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (\u2212\/\u2212) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, <jats:italic>SPNS1<\/jats:italic> overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (\u2212\/\u2212) cells. In addition, we found a reduction in endogenous <jats:italic>SPNS1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-017-15305-9","type":"journal-article","created":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T14:49:18Z","timestamp":1510757358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease"],"prefix":"10.1038","volume":"7","author":[{"given":"Hiroko","family":"Yanagisawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiko","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Nagao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Miyashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Watabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikatsu","family":"Eto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,21]]},"reference":[{"key":"15305_CR1","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","volume":"147","author":"N Mizushima","year":"2011","unstructured":"Mizushima, N. & Komatsu, M. 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