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Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons
Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308361/ https://www.ncbi.nlm.nih.gov/pubmed/31907392 http://dx.doi.org/10.1038/s41418-019-0487-2 |
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author | Tang, Fu-Lei Zhao, Lu Zhao, Yang Sun, Dong Zhu, Xiao-Juan Mei, Lin Xiong, Wen-Cheng |
author_facet | Tang, Fu-Lei Zhao, Lu Zhao, Yang Sun, Dong Zhu, Xiao-Juan Mei, Lin Xiong, Wen-Cheng |
author_sort | Tang, Fu-Lei |
collection | PubMed |
description | Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35’s function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events. |
format | Online Article Text |
id | pubmed-7308361 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73083612020-06-23 Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons Tang, Fu-Lei Zhao, Lu Zhao, Yang Sun, Dong Zhu, Xiao-Juan Mei, Lin Xiong, Wen-Cheng Cell Death Differ Article Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35’s function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events. Nature Publishing Group UK 2020-01-06 2020-07 /pmc/articles/PMC7308361/ /pubmed/31907392 http://dx.doi.org/10.1038/s41418-019-0487-2 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020 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, Fu-Lei Zhao, Lu Zhao, Yang Sun, Dong Zhu, Xiao-Juan Mei, Lin Xiong, Wen-Cheng Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title | Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title_full | Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title_fullStr | Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title_full_unstemmed | Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title_short | Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons |
title_sort | coupling of terminal differentiation deficit with neurodegenerative pathology in vps35-deficient pyramidal neurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308361/ https://www.ncbi.nlm.nih.gov/pubmed/31907392 http://dx.doi.org/10.1038/s41418-019-0487-2 |
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