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TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis
Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352737/ https://www.ncbi.nlm.nih.gov/pubmed/35790884 http://dx.doi.org/10.1038/s12276-022-00789-x |
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author | Bae, Eun-Jin Choi, Minsun Kim, Jeong Tae Kim, Dong-Kyu Jung, Min Kyo Kim, Changyoun Kim, Tae-Kyung Lee, Jun Sung Jung, Byung Chul Shin, Soo Jean Rhee, Ka Hyun Lee, Seung-Jae |
author_facet | Bae, Eun-Jin Choi, Minsun Kim, Jeong Tae Kim, Dong-Kyu Jung, Min Kyo Kim, Changyoun Kim, Tae-Kyung Lee, Jun Sung Jung, Byung Chul Shin, Soo Jean Rhee, Ka Hyun Lee, Seung-Jae |
author_sort | Bae, Eun-Jin |
collection | PubMed |
description | Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein. |
format | Online Article Text |
id | pubmed-9352737 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93527372022-08-19 TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis Bae, Eun-Jin Choi, Minsun Kim, Jeong Tae Kim, Dong-Kyu Jung, Min Kyo Kim, Changyoun Kim, Tae-Kyung Lee, Jun Sung Jung, Byung Chul Shin, Soo Jean Rhee, Ka Hyun Lee, Seung-Jae Exp Mol Med Article Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein. Nature Publishing Group UK 2022-07-05 /pmc/articles/PMC9352737/ /pubmed/35790884 http://dx.doi.org/10.1038/s12276-022-00789-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Bae, Eun-Jin Choi, Minsun Kim, Jeong Tae Kim, Dong-Kyu Jung, Min Kyo Kim, Changyoun Kim, Tae-Kyung Lee, Jun Sung Jung, Byung Chul Shin, Soo Jean Rhee, Ka Hyun Lee, Seung-Jae TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title_full | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title_fullStr | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title_full_unstemmed | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title_short | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
title_sort | tnf-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352737/ https://www.ncbi.nlm.nih.gov/pubmed/35790884 http://dx.doi.org/10.1038/s12276-022-00789-x |
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