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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2022
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.
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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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