{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:47:28Z","timestamp":1790740048329,"version":"4.1.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in <jats:italic>NPC1<\/jats:italic> and <jats:italic>NPC2<\/jats:italic> genes that result in an accumulation of cholesterol in lysosomes. The majority of children with NPC die in adolescence. Currently, no FDA-approved therapies exist for NPC and the mechanisms of NPC disease are not fully understood. Our recent study and the reports from other laboratories showed that 2-hydroxypropyl-\u03b3-cyclodextrin (HP\u03b3CD) alleviates cholesterol accumulation in NPC1-deficient cells in spite of its low binding affinity for cholesterol. In this study, we explored the cellular changes that are induced upon HP\u03b3CD treatment in NPC1 patient-derived fibroblasts. We show that HP\u03b3CD treatment increases lysosome-ER association and enhances autophagic activity. Our study indicates that HP\u03b3CD induces an activation of the transcription factor EB (TFEB), a master regulator of lysosomal functions and autophagy. Lysosome-ER association could potentially function as conduits for cholesterol transport from lysosomes to the ER. Accumulating evidence suggests a role for autophagy in rescuing the cholesterol accumulation in NPC and other degenerative diseases. Collectively, our findings suggest that HP\u03b3CD restores cellular homeostasis in NPC1-deficient cells via enhancing lysosomal dynamics and functions. Understanding the mechanisms of HP\u03b3CD-induced cellular pathways could contribute to effective NPC therapies.<\/jats:p>","DOI":"10.1038\/s41598-020-65627-4","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T10:02:38Z","timestamp":1590487358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["2-Hydroxypropyl-gamma-cyclodextrin overcomes NPC1 deficiency by enhancing lysosome-ER association and autophagy"],"prefix":"10.1038","volume":"10","author":[{"given":"Ashutosh","family":"Singhal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan S.","family":"Krystofiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Gray","family":"Jerome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeongwoon","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"65627_CR1","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1111\/j.1471-4159.2010.06976.x","volume":"116","author":"AI Rosenbaum","year":"2011","unstructured":"Rosenbaum, A. I. & Maxfield, F. R. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J. neurochemistry 116, 789\u2013795, https:\/\/doi.org\/10.1111\/j.1471-4159.2010.06976.x (2011).","journal-title":"J. neurochemistry"},{"key":"65627_CR2","doi-asserted-by":"publisher","first-page":"4500","DOI":"10.1091\/mbc.E04-05-0432","volume":"15","author":"A Choudhury","year":"2004","unstructured":"Choudhury, A., Sharma, D. K., Marks, D. L. & Pagano, R. E. Elevated endosomal cholesterol levels in Niemann-Pick cells inhibit rab4 and perturb membrane recycling. Mol. Biol. Cell 15, 4500\u20134511, https:\/\/doi.org\/10.1091\/mbc.E04-05-0432 (2004).","journal-title":"Mol. Biol. Cell"},{"key":"65627_CR3","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1111\/j.1600-0854.2006.00513.x","volume":"8","author":"NH Pipalia","year":"2007","unstructured":"Pipalia, N. H., Hao, M., Mukherjee, S. & Maxfield, F. R. Sterol, protein and lipid trafficking in Chinese hamster ovary cells with Niemann-Pick type C1 defect. Traffic 8, 130\u2013141, https:\/\/doi.org\/10.1111\/j.1600-0854.2006.00513.x (2007).","journal-title":"Traffic"},{"key":"65627_CR4","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","volume":"161","author":"JL Goldstein","year":"2015","unstructured":"Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161\u2013172, https:\/\/doi.org\/10.1016\/j.cell.2015.01.036 (2015).","journal-title":"Cell"},{"key":"65627_CR5","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1126\/science.277.5323.228","volume":"277","author":"ED Carstea","year":"1997","unstructured":"Carstea, E. D. et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228\u2013231 (1997).","journal-title":"Science"},{"key":"65627_CR6","doi-asserted-by":"publisher","first-page":"2298","DOI":"10.1126\/science.290.5500.2298","volume":"290","author":"S Naureckiene","year":"2000","unstructured":"Naureckiene, S. et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298\u20132301, https:\/\/doi.org\/10.1126\/science.290.5500.2298 (2000).","journal-title":"Science"},{"key":"65627_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/mgme.1999.2882","volume":"68","author":"ME Higgins","year":"1999","unstructured":"Higgins, M. E., Davies, J. P., Chen, F. W. & Ioannou, Y. A. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol. Genet. Metab. 68, 1\u201313, https:\/\/doi.org\/10.1006\/mgme.1999.2882 (1999).","journal-title":"Mol. Genet. Metab."},{"key":"65627_CR8","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.bbalip.2004.08.007","volume":"1685","author":"MT Vanier","year":"2004","unstructured":"Vanier, M. T. & Millat, G. Structure and function of the NPC2 protein. Biochim. Biophys. Acta 1685, 14\u201321, https:\/\/doi.org\/10.1016\/j.bbalip.2004.08.007 (2004).","journal-title":"Biochim. Biophys. Acta"},{"key":"65627_CR9","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/S1388-1981(00)00158-X","volume":"1529","author":"DS Ory","year":"2000","unstructured":"Ory, D. S. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim. Biophys. Acta 1529, 331\u2013339 (2000).","journal-title":"Biochim. Biophys. Acta"},{"key":"65627_CR10","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.brainres.2016.03.035","volume":"1649","author":"ML Schultz","year":"2016","unstructured":"Schultz, M. L., Krus, K. L. & Lieberman, A. P. Lysosome and endoplasmic reticulum quality control pathways in Niemann-Pick type C disease. Brain Res. 1649, 181\u2013188, https:\/\/doi.org\/10.1016\/j.brainres.2016.03.035 (2016).","journal-title":"Brain Res."},{"key":"65627_CR11","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1080\/15548627.2017.1329081","volume":"13","author":"S Dai","year":"2017","unstructured":"Dai, S. et al. Methyl-beta-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy 13, 1435\u20131451, https:\/\/doi.org\/10.1080\/15548627.2017.1329081 (2017).","journal-title":"Autophagy"},{"key":"65627_CR12","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.bbadis.2008.10.002","volume":"1782","author":"NB Nedelsky","year":"2008","unstructured":"Nedelsky, N. B., Todd, P. K. & Taylor, J. P. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim. Biophys. Acta 1782, 691\u2013699, https:\/\/doi.org\/10.1016\/j.bbadis.2008.10.002 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"65627_CR13","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41556-018-0244-7","volume":"21","author":"RE Lawrence","year":"2019","unstructured":"Lawrence, R. E. & Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133\u2013142, https:\/\/doi.org\/10.1038\/s41556-018-0244-7 (2019).","journal-title":"Nat. Cell Biol."},{"key":"65627_CR14","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/nature05291","volume":"443","author":"DC Rubinsztein","year":"2006","unstructured":"Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780\u2013786, https:\/\/doi.org\/10.1038\/nature05291 (2006).","journal-title":"Nature"},{"key":"65627_CR15","doi-asserted-by":"publisher","first-page":"4329","DOI":"10.1242\/jcs.196287","volume":"129","author":"J Pu","year":"2016","unstructured":"Pu, J., Guardia, C. M., Keren-Kaplan, T. & Bonifacino, J. S. Mechanisms and functions of lysosome positioning. J. Cell Sci. 129, 4329\u20134339, https:\/\/doi.org\/10.1242\/jcs.196287 (2016).","journal-title":"J. Cell Sci."},{"key":"65627_CR16","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1126\/science.1174447","volume":"325","author":"M Sardiello","year":"2009","unstructured":"Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473\u2013477, https:\/\/doi.org\/10.1126\/science.1174447 (2009).","journal-title":"Science"},{"key":"65627_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ceb.2017.01.008","volume":"47","author":"JS Bonifacino","year":"2017","unstructured":"Bonifacino, J. S. & Neefjes, J. Moving and positioning the endolysosomal system. Curr. Opin. Cell Biol. 47, 1\u20138, https:\/\/doi.org\/10.1016\/j.ceb.2017.01.008 (2017).","journal-title":"Curr. Opin. Cell Biol."},{"key":"65627_CR18","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1038\/346864a0","volume":"346","author":"PJ Hollenbeck","year":"1990","unstructured":"Hollenbeck, P. J. & Swanson, J. A. Radial extension of macrophage tubular lysosomes supported by kinesin. Nature 346, 864\u2013866, https:\/\/doi.org\/10.1038\/346864a0 (1990).","journal-title":"Nature"},{"key":"65627_CR19","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1083\/jcb.141.1.51","volume":"141","author":"A Harada","year":"1998","unstructured":"Harada, A. et al. Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein. J. Cell Biol. 141, 51\u201359 (1998).","journal-title":"J. Cell Biol."},{"key":"65627_CR20","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1093\/emboj\/21.6.1289","volume":"21","author":"C Lebrand","year":"2002","unstructured":"Lebrand, C. et al. Late endosome motility depends on lipids via the small GTPase Rab7. Embo j. 21, 1289\u20131300, https:\/\/doi.org\/10.1093\/emboj\/21.6.1289 (2002).","journal-title":"Embo j."},{"key":"65627_CR21","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1091\/mbc.12.3.601","volume":"12","author":"DC Ko","year":"2001","unstructured":"Ko, D. C., Gordon, M. D., Jin, J. Y. & Scott, M. P. Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601\u2013614 (2001).","journal-title":"Mol. Biol. Cell"},{"key":"65627_CR22","doi-asserted-by":"publisher","first-page":"4466","DOI":"10.1073\/pnas.081070898","volume":"98","author":"M Zhang","year":"2001","unstructured":"Zhang, M. et al. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease. Proc. Natl Acad. Sci. USA 98, 4466\u20134471, https:\/\/doi.org\/10.1073\/pnas.081070898 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"65627_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1056-1","volume":"9","author":"A Singhal","year":"2018","unstructured":"Singhal, A., Szente, L., Hildreth, J. E. K. & Song, B. Hydroxypropyl-beta and -gamma cyclodextrins rescue cholesterol accumulation in Niemann-Pick C1 mutant cell via lysosome-associated membrane protein 1. Cell death Dis. 9, 1019, https:\/\/doi.org\/10.1038\/s41419-018-1056-1 (2018).","journal-title":"Cell death Dis."},{"key":"65627_CR24","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1016\/j.bbalip.2016.01.020","volume":"1861","author":"ER Eden","year":"2016","unstructured":"Eden, E. R. The formation and function of ER-endosome membrane contact sites. Biochim. Biophys. Acta 1861, 874\u2013879, https:\/\/doi.org\/10.1016\/j.bbalip.2016.01.020 (2016).","journal-title":"Biochim. Biophys. Acta"},{"key":"65627_CR25","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1097\/mol.0000000000000292","volume":"27","author":"SG Pfisterer","year":"2016","unstructured":"Pfisterer, S. G., Peranen, J. & Ikonen, E. LDL-cholesterol transport to the endoplasmic reticulum: current concepts. Curr. Opin. Lipidol. 27, 282\u2013287, https:\/\/doi.org\/10.1097\/mol.0000000000000292 (2016).","journal-title":"Curr. Opin. Lipidol."},{"key":"65627_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12152-2","volume":"10","author":"D Hoglinger","year":"2019","unstructured":"Hoglinger, D. et al. NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nat. Commun. 10, 4276, https:\/\/doi.org\/10.1038\/s41467-019-12152-2 (2019).","journal-title":"Nat. Commun."},{"key":"65627_CR27","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1194\/jlr.M700525-JLR200","volume":"49","author":"B Liu","year":"2008","unstructured":"Liu, B., Li, H., Repa, J. J., Turley, S. D. & Dietschy, J. M. Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J. Lipid Res. 49, 663\u2013669, https:\/\/doi.org\/10.1194\/jlr.M700525-JLR200 (2008).","journal-title":"J. Lipid Res."},{"key":"65627_CR28","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1073\/pnas.0810895106","volume":"106","author":"B Liu","year":"2009","unstructured":"Liu, B. et al. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1\u2212\/\u2212 mouse. Proc. Natl Acad. Sci. USA 106, 2377\u20132382, https:\/\/doi.org\/10.1073\/pnas.0810895106 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"65627_CR29","doi-asserted-by":"publisher","first-page":"e6951","DOI":"10.1371\/journal.pone.0006951","volume":"4","author":"CD Davidson","year":"2009","unstructured":"Davidson, C. D. et al. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4, e6951, https:\/\/doi.org\/10.1371\/journal.pone.0006951 (2009).","journal-title":"PLoS One"},{"key":"65627_CR30","doi-asserted-by":"publisher","first-page":"9404","DOI":"10.1523\/jneurosci.1317-11.2011","volume":"31","author":"A Aqul","year":"2011","unstructured":"Aqul, A. et al. Unesterified cholesterol accumulation in late endosomes\/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J. neuroscience: Off. J. Soc. Neurosci. 31, 9404\u20139413, https:\/\/doi.org\/10.1523\/jneurosci.1317-11.2011 (2011).","journal-title":"J. neuroscience: Off. J. Soc. Neurosci."},{"key":"65627_CR31","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ymgme.2012.11.005","volume":"108","author":"M Matsuo","year":"2013","unstructured":"Matsuo, M. et al. Effects of cyclodextrin in two patients with Niemann-Pick Type C disease. Mol. Genet. Metab. 108, 76\u201381, https:\/\/doi.org\/10.1016\/j.ymgme.2012.11.005 (2013).","journal-title":"Mol. Genet. Metab."},{"key":"65627_CR32","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ymgme.2015.07.001","volume":"116","author":"TJ Maarup","year":"2015","unstructured":"Maarup, T. J. et al. Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann-Pick C1. Mol. Genet. Metab. 116, 75\u201379, https:\/\/doi.org\/10.1016\/j.ymgme.2015.07.001 (2015).","journal-title":"Mol. Genet. Metab."},{"key":"65627_CR33","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1203\/PDR.0b013e3181df4623","volume":"68","author":"S Ward","year":"2010","unstructured":"Ward, S., O\u2019Donnell, P., Fernandez, S. & Vite, C. H. 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatric Res. 68, 52\u201356, https:\/\/doi.org\/10.1203\/PDR.0b013e3181df4623 (2010).","journal-title":"Pediatric Res."},{"key":"65627_CR34","doi-asserted-by":"publisher","first-page":"e53280","DOI":"10.1371\/journal.pone.0053280","volume":"7","author":"MA Crumling","year":"2012","unstructured":"Crumling, M. A. et al. Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-beta-cyclodextrin. PLoS One 7, e53280, https:\/\/doi.org\/10.1371\/journal.pone.0053280 (2012).","journal-title":"PLoS One"},{"key":"65627_CR35","doi-asserted-by":"publisher","first-page":"276ra226","DOI":"10.1126\/scitranslmed.3010101","volume":"7","author":"CH Vite","year":"2015","unstructured":"Vite, C. H. et al. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci. Transl. Med. 7, 276ra226, https:\/\/doi.org\/10.1126\/scitranslmed.3010101 (2015).","journal-title":"Sci. Transl. Med."},{"key":"65627_CR36","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1002\/stem.1917","volume":"33","author":"M Soga","year":"2015","unstructured":"Soga, M. et al. HPGCD outperforms HPBCD as a potential treatment for Niemann-Pick disease type C during disease modeling with iPS cells. Stem Cell 33, 1075\u20131088, https:\/\/doi.org\/10.1002\/stem.1917 (2015).","journal-title":"Stem Cell"},{"key":"65627_CR37","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1002\/acn3.306","volume":"3","author":"CD Davidson","year":"2016","unstructured":"Davidson, C. D. et al. Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Ann. Clin. Transl. Neurol. 3, 366\u2013380, https:\/\/doi.org\/10.1002\/acn3.306 (2016).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"65627_CR38","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.3390\/molecules23051228","volume":"23","author":"L Szente","year":"2018","unstructured":"Szente, L., Singhal, A., Domokos, A. & Song, B. Cyclodextrins: Assessing the Impact of Cavity Size, Occupancy, and Substitutions on Cytotoxicity and Cholesterol Homeostasis. Molecules 23, 1228 (2018).","journal-title":"Molecules"},{"key":"65627_CR39","doi-asserted-by":"publisher","first-page":"3965054","DOI":"10.1155\/2018\/3965054","volume":"2018","author":"DY Litvinov","year":"2018","unstructured":"Litvinov, D. Y., Savushkin, E. V. & Dergunov, A. D. Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis. J. lipids 2018, 3965054, https:\/\/doi.org\/10.1155\/2018\/3965054 (2018).","journal-title":"J. lipids"},{"key":"65627_CR40","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1111\/tra.12471","volume":"18","author":"J Luo","year":"2017","unstructured":"Luo, J., Jiang, L., Yang, H. & Song, B. L. Routes and mechanisms of post-endosomal cholesterol trafficking: A story that never ends. Traffic 18, 209\u2013217, https:\/\/doi.org\/10.1111\/tra.12471 (2017).","journal-title":"Traffic"},{"key":"65627_CR41","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S1534-5807(04)00099-1","volume":"6","author":"B Levine","year":"2004","unstructured":"Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Developmental Cell 6, 463\u2013477 (2004).","journal-title":"Developmental Cell"},{"key":"65627_CR42","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","volume":"19","author":"Y Kabeya","year":"2000","unstructured":"Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo j. 19, 5720\u20135728, https:\/\/doi.org\/10.1093\/emboj\/19.21.5720 (2000).","journal-title":"Embo j."},{"key":"65627_CR43","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1091\/mbc.e03-09-0704","volume":"15","author":"N Mizushima","year":"2004","unstructured":"Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101\u20131111, https:\/\/doi.org\/10.1091\/mbc.e03-09-0704 (2004).","journal-title":"Mol. Biol. Cell"},{"key":"65627_CR44","doi-asserted-by":"publisher","first-page":"10211","DOI":"10.1074\/jbc.M113.506246","volume":"289","author":"W Song","year":"2014","unstructured":"Song, W., Wang, F., Lotfi, P., Sardiello, M. & Segatori, L. 2-Hydroxypropyl-beta-cyclodextrin promotes transcription factor EB-mediated activation of autophagy: implications for therapy. J. Biol. Chem. 289, 10211\u201310222, https:\/\/doi.org\/10.1074\/jbc.M113.506246 (2014).","journal-title":"J. Biol. Chem."},{"key":"65627_CR45","doi-asserted-by":"publisher","first-page":"17054","DOI":"10.1074\/jbc.M114.555300","volume":"289","author":"M Moskot","year":"2014","unstructured":"Moskot, M. et al. The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J. Biol. Chem. 289, 17054\u201317069, https:\/\/doi.org\/10.1074\/jbc.M114.555300 (2014).","journal-title":"J. Biol. Chem."},{"key":"65627_CR46","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1007\/s12017-018-8482-1","volume":"20","author":"K Pierzynowska","year":"2018","unstructured":"Pierzynowska, K. et al. Correction of Huntington\u2019s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model. Neuromolecular Med. 20, 112\u2013123, https:\/\/doi.org\/10.1007\/s12017-018-8482-1 (2018).","journal-title":"Neuromolecular Med."},{"key":"65627_CR47","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/nrm.2015.8","volume":"17","author":"MJ Phillips","year":"2016","unstructured":"Phillips, M. J. & Voeltz, G. K. Structure and function of ER membrane contact sites with other organelles. Nat. reviews. Mol. Cell Biol. 17, 69\u201382, https:\/\/doi.org\/10.1038\/nrm.2015.8 (2016).","journal-title":"Nat. reviews. Mol. Cell Biol."},{"key":"65627_CR48","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.15252\/embj.201591481","volume":"34","author":"C Raiborg","year":"2015","unstructured":"Raiborg, C., Wenzel, E. M. & Stenmark, H. ER-endosome contact sites: molecular compositions and functions. Embo j. 34, 1848\u20131858, https:\/\/doi.org\/10.15252\/embj.201591481 (2015).","journal-title":"Embo j."},{"key":"65627_CR49","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1242\/jcs.137539","volume":"127","author":"R van der Kant","year":"2014","unstructured":"van der Kant, R. & Neefjes, J. Small regulators, major consequences - Ca(2)(+) and cholesterol at the endosome-ER interface. J. Cell Sci. 127, 929\u2013938, https:\/\/doi.org\/10.1242\/jcs.137539 (2014).","journal-title":"J. Cell Sci."},{"key":"65627_CR50","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1080\/15548627.2018.1438807","volume":"14","author":"E Barbero-Camps","year":"2018","unstructured":"Barbero-Camps, E. et al. Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy 14, 1129\u20131154, https:\/\/doi.org\/10.1080\/15548627.2018.1438807 (2018).","journal-title":"Autophagy"},{"key":"65627_CR51","doi-asserted-by":"publisher","first-page":"3936","DOI":"10.1073\/pnas.1717338115","volume":"115","author":"M Hata","year":"2018","unstructured":"Hata, M. et al. Reduction of lipid accumulation rescues Bietti\u2019s crystalline dystrophy phenotypes. Proc. Natl Acad. Sci. USA 115, 3936\u20133941, https:\/\/doi.org\/10.1073\/pnas.1717338115 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"65627_CR52","doi-asserted-by":"publisher","first-page":"5477","DOI":"10.1073\/pnas.0914309107","volume":"107","author":"AI Rosenbaum","year":"2010","unstructured":"Rosenbaum, A. I., Zhang, G., Warren, J. D. & Maxfield, F. R. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc. Natl Acad. Sci. USA 107, 5477\u20135482, https:\/\/doi.org\/10.1073\/pnas.0914309107 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"65627_CR53","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ijpharm.2010.09.032","volume":"403","author":"H Wei","year":"2011","unstructured":"Wei, H., Zheng, W., Diakur, J. & Wiebe, L. I. Confocal laser scanning microscopy (CLSM) based evidence for cell permeation by mono-4-(N-6-deoxy-6-amino-beta-cyclodextrin)-7-nitrobenzofuran (NBD-beta-CyD). Int. J. Pharm. 403, 15\u201322, https:\/\/doi.org\/10.1016\/j.ijpharm.2010.09.032 (2011).","journal-title":"Int. J. Pharm."},{"issue":"1-2","key":"65627_CR54","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ijpharm.2011.04.021","volume":"413","author":"Martin J. O\u2019 Neill","year":"2011","unstructured":"MJ, O. N., Guo, J., Byrne, C., Darcy, R. & CM, O. D. Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells. Int J Pharm 413, 174\u2013183, https:\/\/doi.org\/10.1016\/j.ijpharm.2011.04.021 (2011).","journal-title":"International Journal of Pharmaceutics"},{"key":"65627_CR55","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.chemphyslip.2012.03.007","volume":"165","author":"AP Plazzo","year":"2012","unstructured":"Plazzo, A. P. et al. Uptake of a fluorescent methyl-beta-cyclodextrin via clathrin-dependent endocytosis. Chem. Phys. Lipids 165, 505\u2013511, https:\/\/doi.org\/10.1016\/j.chemphyslip.2012.03.007 (2012).","journal-title":"Chem. Phys. Lipids"},{"key":"65627_CR56","doi-asserted-by":"publisher","first-page":"e84856","DOI":"10.1371\/journal.pone.0084856","volume":"9","author":"F Fenyvesi","year":"2014","unstructured":"Fenyvesi, F. et al. Fluorescently labeled methyl-beta-cyclodextrin enters intestinal epithelial Caco-2 cells by fluid-phase endocytosis. PLoS One 9, e84856, https:\/\/doi.org\/10.1371\/journal.pone.0084856 (2014).","journal-title":"PLoS One"},{"key":"65627_CR57","doi-asserted-by":"publisher","first-page":"9607","DOI":"10.1523\/jneurosci.3788-13.2014","volume":"34","author":"Q Xiao","year":"2014","unstructured":"Xiao, Q. et al. Enhancing astrocytic lysosome biogenesis facilitates Abeta clearance and attenuates amyloid plaque pathogenesis. J. neuroscience: Off. J. Soc. Neurosci. 34, 9607\u20139620, https:\/\/doi.org\/10.1523\/jneurosci.3788-13.2014 (2014).","journal-title":"J. neuroscience: Off. J. Soc. Neurosci."},{"key":"65627_CR58","doi-asserted-by":"publisher","first-page":"12137","DOI":"10.1523\/jneurosci.0705-15.2015","volume":"35","author":"Q Xiao","year":"2015","unstructured":"Xiao, Q. et al. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Abeta Generation and Amyloid Plaque Pathogenesis. J. neuroscience: Off. J. Soc. Neurosci. 35, 12137\u201312151, https:\/\/doi.org\/10.1523\/jneurosci.0705-15.2015 (2015).","journal-title":"J. neuroscience: Off. J. Soc. Neurosci."},{"key":"65627_CR59","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.15252\/emmm.201303671","volume":"6","author":"VA Polito","year":"2014","unstructured":"Polito, V. A. et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol. Med. 6, 1142\u20131160, https:\/\/doi.org\/10.15252\/emmm.201303671 (2014).","journal-title":"EMBO Mol. Med."},{"key":"65627_CR60","doi-asserted-by":"publisher","first-page":"E1817","DOI":"10.1073\/pnas.1305623110","volume":"110","author":"M Decressac","year":"2013","unstructured":"Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817\u20131826, https:\/\/doi.org\/10.1073\/pnas.1305623110 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"65627_CR61","doi-asserted-by":"publisher","first-page":"142ra197","DOI":"10.1126\/scitranslmed.3003799","volume":"4","author":"T Tsunemi","year":"2012","unstructured":"Tsunemi, T. et al. PGC-1alpha rescues Huntington\u2019s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra197, https:\/\/doi.org\/10.1126\/scitranslmed.3003799 (2012).","journal-title":"Sci. Transl. Med."},{"key":"65627_CR62","doi-asserted-by":"crossref","unstructured":"Ellis, E. A. Solutions to the Problem of Substitution of ERL 4221 for Vinyl Cyclohexene Dioxide in Spurr Low Viscosity Embedding Formulations Microscopy Today 14 (2006).","DOI":"10.1017\/S1551929500050252"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65627-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65627-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65627-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T11:31:46Z","timestamp":1670326306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65627-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,26]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["65627"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-65627-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,26]]},"assertion":[{"value":"21 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8663"}}