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StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival
The pathological accumulation of cholesterol is a signature feature of Niemann–Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late e...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203878/ https://www.ncbi.nlm.nih.gov/pubmed/36861884 http://dx.doi.org/10.1242/jcs.260662 |
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author | Sterling, Felicity R. D'Amico, Jon Brumfield, Alexandria M. Huegel, Kara L. Vaughan, Patricia S. Morris, Kathryn Schwarz, Shelby Joyce, Michelle V. Boggess, Bill Champion, Matthew M. Maciuba, Kevin Allen, Philip Marasco, Eric Koch, Grant Gonzalez, Peter Hodges, Shannon Leahy, Shannon Gerstbauer, Erica Hinchcliffe, Edward H. Vaughan, Kevin T. |
author_facet | Sterling, Felicity R. D'Amico, Jon Brumfield, Alexandria M. Huegel, Kara L. Vaughan, Patricia S. Morris, Kathryn Schwarz, Shelby Joyce, Michelle V. Boggess, Bill Champion, Matthew M. Maciuba, Kevin Allen, Philip Marasco, Eric Koch, Grant Gonzalez, Peter Hodges, Shannon Leahy, Shannon Gerstbauer, Erica Hinchcliffe, Edward H. Vaughan, Kevin T. |
author_sort | Sterling, Felicity R. |
collection | PubMed |
description | The pathological accumulation of cholesterol is a signature feature of Niemann–Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease. |
format | Online Article Text |
id | pubmed-10203878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-102038782023-05-24 StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival Sterling, Felicity R. D'Amico, Jon Brumfield, Alexandria M. Huegel, Kara L. Vaughan, Patricia S. Morris, Kathryn Schwarz, Shelby Joyce, Michelle V. Boggess, Bill Champion, Matthew M. Maciuba, Kevin Allen, Philip Marasco, Eric Koch, Grant Gonzalez, Peter Hodges, Shannon Leahy, Shannon Gerstbauer, Erica Hinchcliffe, Edward H. Vaughan, Kevin T. J Cell Sci Research Article The pathological accumulation of cholesterol is a signature feature of Niemann–Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease. The Company of Biologists Ltd 2023-03-02 /pmc/articles/PMC10203878/ /pubmed/36861884 http://dx.doi.org/10.1242/jcs.260662 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Sterling, Felicity R. D'Amico, Jon Brumfield, Alexandria M. Huegel, Kara L. Vaughan, Patricia S. Morris, Kathryn Schwarz, Shelby Joyce, Michelle V. Boggess, Bill Champion, Matthew M. Maciuba, Kevin Allen, Philip Marasco, Eric Koch, Grant Gonzalez, Peter Hodges, Shannon Leahy, Shannon Gerstbauer, Erica Hinchcliffe, Edward H. Vaughan, Kevin T. StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title | StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title_full | StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title_fullStr | StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title_full_unstemmed | StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title_short | StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival |
title_sort | stard9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and purkinje cell survival |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203878/ https://www.ncbi.nlm.nih.gov/pubmed/36861884 http://dx.doi.org/10.1242/jcs.260662 |
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