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The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease
Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We e...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943320/ https://www.ncbi.nlm.nih.gov/pubmed/35300522 http://dx.doi.org/10.1177/17590914221087817 |
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author | Reiter, Cory R. Rebiai, Rima Kwak, Angelika Marshall, Jeff Wozniak, Dylan Scesa, Giusepe Nguyen, Duc Rue, Emily Pathmasiri, Chandimal Pijewski, Robert van Breemen, Richard Cologna, Stephanie Crocker, Stephen J. Givogri, M Irene Bongarzone, Ernesto R |
author_facet | Reiter, Cory R. Rebiai, Rima Kwak, Angelika Marshall, Jeff Wozniak, Dylan Scesa, Giusepe Nguyen, Duc Rue, Emily Pathmasiri, Chandimal Pijewski, Robert van Breemen, Richard Cologna, Stephanie Crocker, Stephen J. Givogri, M Irene Bongarzone, Ernesto R |
author_sort | Reiter, Cory R. |
collection | PubMed |
description | Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity. Notably, characterization of well-established, neuroanatomic hallmarks of disease pathology, such as demyelination and inflammatory gliosis, remained essentially unaltered in the brains of GW4869-treated Twitcher mice compared to vehicle-treated Twitcher controls. Further analysis of Twitcher brain pathophysiology is required to understand the mechanism behind early-onset disease severity in GW4869-treated mice. The results herein demonstrate that some pathogenic lipids like psychosine may be secreted using EV pathways. Our results highlight the relevance of this secretory mechanism as a possible contributor to spreading pathogenic lipids in neurological lipidoses. |
format | Online Article Text |
id | pubmed-8943320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-89433202022-03-25 The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease Reiter, Cory R. Rebiai, Rima Kwak, Angelika Marshall, Jeff Wozniak, Dylan Scesa, Giusepe Nguyen, Duc Rue, Emily Pathmasiri, Chandimal Pijewski, Robert van Breemen, Richard Cologna, Stephanie Crocker, Stephen J. Givogri, M Irene Bongarzone, Ernesto R ASN Neuro Original Paper Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity. Notably, characterization of well-established, neuroanatomic hallmarks of disease pathology, such as demyelination and inflammatory gliosis, remained essentially unaltered in the brains of GW4869-treated Twitcher mice compared to vehicle-treated Twitcher controls. Further analysis of Twitcher brain pathophysiology is required to understand the mechanism behind early-onset disease severity in GW4869-treated mice. The results herein demonstrate that some pathogenic lipids like psychosine may be secreted using EV pathways. Our results highlight the relevance of this secretory mechanism as a possible contributor to spreading pathogenic lipids in neurological lipidoses. SAGE Publications 2022-03-18 /pmc/articles/PMC8943320/ /pubmed/35300522 http://dx.doi.org/10.1177/17590914221087817 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Paper Reiter, Cory R. Rebiai, Rima Kwak, Angelika Marshall, Jeff Wozniak, Dylan Scesa, Giusepe Nguyen, Duc Rue, Emily Pathmasiri, Chandimal Pijewski, Robert van Breemen, Richard Cologna, Stephanie Crocker, Stephen J. Givogri, M Irene Bongarzone, Ernesto R The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title | The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title_full | The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title_fullStr | The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title_full_unstemmed | The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title_short | The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease |
title_sort | pathogenic sphingolipid psychosine is secreted in extracellular vesicles in the brain of a mouse model of krabbe disease |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943320/ https://www.ncbi.nlm.nih.gov/pubmed/35300522 http://dx.doi.org/10.1177/17590914221087817 |
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