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Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons
BACKGROUND: Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the en...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459568/ https://www.ncbi.nlm.nih.gov/pubmed/34551802 http://dx.doi.org/10.1186/s12974-021-02272-2 |
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author | Brunialti, Electra Villa, Alessandro Mekhaeil, Marianna Mornata, Federica Vegeto, Elisabetta Maggi, Adriana Di Monte, Donato A. Ciana, Paolo |
author_facet | Brunialti, Electra Villa, Alessandro Mekhaeil, Marianna Mornata, Federica Vegeto, Elisabetta Maggi, Adriana Di Monte, Donato A. Ciana, Paolo |
author_sort | Brunialti, Electra |
collection | PubMed |
description | BACKGROUND: Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. METHODS: We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. RESULTS: Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. CONCLUSION: This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02272-2. |
format | Online Article Text |
id | pubmed-8459568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-84595682021-09-23 Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons Brunialti, Electra Villa, Alessandro Mekhaeil, Marianna Mornata, Federica Vegeto, Elisabetta Maggi, Adriana Di Monte, Donato A. Ciana, Paolo J Neuroinflammation Research BACKGROUND: Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. METHODS: We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. RESULTS: Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. CONCLUSION: This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02272-2. BioMed Central 2021-09-22 /pmc/articles/PMC8459568/ /pubmed/34551802 http://dx.doi.org/10.1186/s12974-021-02272-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Brunialti, Electra Villa, Alessandro Mekhaeil, Marianna Mornata, Federica Vegeto, Elisabetta Maggi, Adriana Di Monte, Donato A. Ciana, Paolo Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title | Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title_full | Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title_fullStr | Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title_full_unstemmed | Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title_short | Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
title_sort | inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459568/ https://www.ncbi.nlm.nih.gov/pubmed/34551802 http://dx.doi.org/10.1186/s12974-021-02272-2 |
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