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Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration

Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating...

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Autores principales: Kreher, Conlan, Favret, Jacob, Weinstock, Nadav I., Maulik, Malabika, Hong, Xinying, Gelb, Michael H., Wrabetz, Lawrence, Feltri, M. Laura, Shin, Daesung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255775/
https://www.ncbi.nlm.nih.gov/pubmed/35789331
http://dx.doi.org/10.1371/journal.pbio.3001661
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author Kreher, Conlan
Favret, Jacob
Weinstock, Nadav I.
Maulik, Malabika
Hong, Xinying
Gelb, Michael H.
Wrabetz, Lawrence
Feltri, M. Laura
Shin, Daesung
author_facet Kreher, Conlan
Favret, Jacob
Weinstock, Nadav I.
Maulik, Malabika
Hong, Xinying
Gelb, Michael H.
Wrabetz, Lawrence
Feltri, M. Laura
Shin, Daesung
author_sort Kreher, Conlan
collection PubMed
description Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. Confocal and electron microscopic analyses show profound neuro-axonal degeneration with a mild effect on myelin structure. Thus, we prove for the first time that neuronal GALC is essential to maintain and protect neuronal function independently of myelin and may directly contribute to the pathogenesis of Krabbe disease.
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spelling pubmed-92557752022-07-06 Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration Kreher, Conlan Favret, Jacob Weinstock, Nadav I. Maulik, Malabika Hong, Xinying Gelb, Michael H. Wrabetz, Lawrence Feltri, M. Laura Shin, Daesung PLoS Biol Research Article Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. Confocal and electron microscopic analyses show profound neuro-axonal degeneration with a mild effect on myelin structure. Thus, we prove for the first time that neuronal GALC is essential to maintain and protect neuronal function independently of myelin and may directly contribute to the pathogenesis of Krabbe disease. Public Library of Science 2022-07-05 /pmc/articles/PMC9255775/ /pubmed/35789331 http://dx.doi.org/10.1371/journal.pbio.3001661 Text en © 2022 Kreher et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kreher, Conlan
Favret, Jacob
Weinstock, Nadav I.
Maulik, Malabika
Hong, Xinying
Gelb, Michael H.
Wrabetz, Lawrence
Feltri, M. Laura
Shin, Daesung
Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title_full Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title_fullStr Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title_full_unstemmed Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title_short Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration
title_sort neuron-specific ablation of the krabbe disease gene galactosylceramidase in mice results in neurodegeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255775/
https://www.ncbi.nlm.nih.gov/pubmed/35789331
http://dx.doi.org/10.1371/journal.pbio.3001661
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