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A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface
Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864947/ https://www.ncbi.nlm.nih.gov/pubmed/33547385 http://dx.doi.org/10.1038/s42003-021-01682-5 |
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author | Tang, Cynthia Han, Jimin Dalvi, Sonal Manian, Kannan Winschel, Lauren Volland, Stefanie Soto, Celia A. Galloway, Chad A. Spencer, Whitney Roll, Michael Milliner, Caroline Bonilha, Vera L. Johnson, Tyler B. Latchney, Lisa Weimer, Jill M. Augustine, Erika F. Mink, Jonathan W. Gullapalli, Vamsi K. Chung, Mina Williams, David S. Singh, Ruchira |
author_facet | Tang, Cynthia Han, Jimin Dalvi, Sonal Manian, Kannan Winschel, Lauren Volland, Stefanie Soto, Celia A. Galloway, Chad A. Spencer, Whitney Roll, Michael Milliner, Caroline Bonilha, Vera L. Johnson, Tyler B. Latchney, Lisa Weimer, Jill M. Augustine, Erika F. Mink, Jonathan W. Gullapalli, Vamsi K. Chung, Mina Williams, David S. Singh, Ruchira |
author_sort | Tang, Cynthia |
collection | PubMed |
description | Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy. |
format | Online Article Text |
id | pubmed-7864947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78649472021-02-16 A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface Tang, Cynthia Han, Jimin Dalvi, Sonal Manian, Kannan Winschel, Lauren Volland, Stefanie Soto, Celia A. Galloway, Chad A. Spencer, Whitney Roll, Michael Milliner, Caroline Bonilha, Vera L. Johnson, Tyler B. Latchney, Lisa Weimer, Jill M. Augustine, Erika F. Mink, Jonathan W. Gullapalli, Vamsi K. Chung, Mina Williams, David S. Singh, Ruchira Commun Biol Article Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy. Nature Publishing Group UK 2021-02-05 /pmc/articles/PMC7864947/ /pubmed/33547385 http://dx.doi.org/10.1038/s42003-021-01682-5 Text en © The Author(s) 2021 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 Tang, Cynthia Han, Jimin Dalvi, Sonal Manian, Kannan Winschel, Lauren Volland, Stefanie Soto, Celia A. Galloway, Chad A. Spencer, Whitney Roll, Michael Milliner, Caroline Bonilha, Vera L. Johnson, Tyler B. Latchney, Lisa Weimer, Jill M. Augustine, Erika F. Mink, Jonathan W. Gullapalli, Vamsi K. Chung, Mina Williams, David S. Singh, Ruchira A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title | A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title_full | A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title_fullStr | A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title_full_unstemmed | A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title_short | A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface |
title_sort | human model of batten disease shows role of cln3 in phagocytosis at the photoreceptor–rpe interface |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864947/ https://www.ncbi.nlm.nih.gov/pubmed/33547385 http://dx.doi.org/10.1038/s42003-021-01682-5 |
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