{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:29:29Z","timestamp":1792805369608,"version":"4.5.0"},"reference-count":66,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["IP-2016-06-2799"],"award-info":[{"award-number":["IP-2016-06-2799"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EXC 2145 SyNergy\u2013 ID 390857198"],"award-info":[{"award-number":["EXC 2145 SyNergy\u2013 ID 390857198"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer\u2019s Association Grant through the AD Strategic Fund","award":["ADSF-21-831226-C"],"award-info":[{"award-number":["ADSF-21-831226-C"]}],"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB\/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and\/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC.<\/jats:p>","DOI":"10.3390\/ijms222413256","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:46:58Z","timestamp":1639086418000},"page":"13256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation"],"prefix":"10.3390","volume":"22","author":[{"given":"Kristina","family":"Dominko","sequence":"first","affiliation":[{"name":"Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Rastija","sequence":"additional","affiliation":[{"name":"Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8915-6009","authenticated-orcid":false,"given":"Sandra","family":"Sobocanec","sequence":"additional","affiliation":[{"name":"Laboratory for Mitochondrial Bioenergetics and Diabetes, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Vidatic","sequence":"additional","affiliation":[{"name":"Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5143-7913","authenticated-orcid":false,"given":"Sarah","family":"Meglaj","sequence":"additional","affiliation":[{"name":"Division of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lovincic Babic","sequence":"additional","affiliation":[{"name":"Division of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Hutter-Paier","sequence":"additional","affiliation":[{"name":"QPS Austria GmbH, 8074 Grambach, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio-Vittorio","family":"Colombo","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-2575","authenticated-orcid":false,"given":"Stefan F.","family":"Lichtenthaler","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"},{"name":"Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4403-9559","authenticated-orcid":false,"given":"Sabina","family":"Tahirovic","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-433X","authenticated-orcid":false,"given":"Silva","family":"Hecimovic","sequence":"additional","affiliation":[{"name":"Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6142","DOI":"10.1523\/JNEUROSCI.17-16-06142.1997","article-title":"Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer\u2019s Disease: Neuropathologic Evidence for a Mechanism of Increased \u03b2-Amyloidogenesis","volume":"17","author":"Cataldo","year":"1997","journal-title":"J. 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