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Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease,...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395532/ https://www.ncbi.nlm.nih.gov/pubmed/35995799 http://dx.doi.org/10.1038/s41467-022-32625-1 |
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author | Xie, Ying Xue Naseri, Nima N. Fels, Jasmine Kharel, Parinati Na, Yoonmi Lane, Diane Burré, Jacqueline Sharma, Manu |
author_facet | Xie, Ying Xue Naseri, Nima N. Fels, Jasmine Kharel, Parinati Na, Yoonmi Lane, Diane Burré, Jacqueline Sharma, Manu |
author_sort | Xie, Ying Xue |
collection | PubMed |
description | Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca(2+). These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons. |
format | Online Article Text |
id | pubmed-9395532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93955322022-08-24 Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models Xie, Ying Xue Naseri, Nima N. Fels, Jasmine Kharel, Parinati Na, Yoonmi Lane, Diane Burré, Jacqueline Sharma, Manu Nat Commun Article Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca(2+). These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons. Nature Publishing Group UK 2022-08-22 /pmc/articles/PMC9395532/ /pubmed/35995799 http://dx.doi.org/10.1038/s41467-022-32625-1 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 Xie, Ying Xue Naseri, Nima N. Fels, Jasmine Kharel, Parinati Na, Yoonmi Lane, Diane Burré, Jacqueline Sharma, Manu Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title | Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title_full | Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title_fullStr | Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title_full_unstemmed | Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title_short | Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
title_sort | lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395532/ https://www.ncbi.nlm.nih.gov/pubmed/35995799 http://dx.doi.org/10.1038/s41467-022-32625-1 |
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