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Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage
This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mut...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Medknow Publications & Media Pvt Ltd
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900492/ https://www.ncbi.nlm.nih.gov/pubmed/29623914 http://dx.doi.org/10.4103/1673-5374.228712 |
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author | Scott-Hewitt, Nicole J. Folts, Christopher J. Noble, Mark D. |
author_facet | Scott-Hewitt, Nicole J. Folts, Christopher J. Noble, Mark D. |
author_sort | Scott-Hewitt, Nicole J. |
collection | PubMed |
description | This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis (MS), another disease characterized by extensive myelin damage. What explains these correlations? In studies on cuprizone-induced myelin damage in heterozygous (GALC(+/–)) mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC(+/–) and wild-type (WT) mice. In contrast, GALC(+/-) mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher (GALC(+/–)) mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair. |
format | Online Article Text |
id | pubmed-5900492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Medknow Publications & Media Pvt Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-59004922018-04-24 Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage Scott-Hewitt, Nicole J. Folts, Christopher J. Noble, Mark D. Neural Regen Res Invited Review This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis (MS), another disease characterized by extensive myelin damage. What explains these correlations? In studies on cuprizone-induced myelin damage in heterozygous (GALC(+/–)) mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC(+/–) and wild-type (WT) mice. In contrast, GALC(+/-) mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher (GALC(+/–)) mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair. Medknow Publications & Media Pvt Ltd 2018-03 /pmc/articles/PMC5900492/ /pubmed/29623914 http://dx.doi.org/10.4103/1673-5374.228712 Text en Copyright: © Neural Regeneration Research http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. |
spellingShingle | Invited Review Scott-Hewitt, Nicole J. Folts, Christopher J. Noble, Mark D. Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title | Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title_full | Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title_fullStr | Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title_full_unstemmed | Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title_short | Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage |
title_sort | heterozygous carriers of galactocerebrosidase mutations that cause krabbe disease have impaired microglial function and defective repair of myelin damage |
topic | Invited Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900492/ https://www.ncbi.nlm.nih.gov/pubmed/29623914 http://dx.doi.org/10.4103/1673-5374.228712 |
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