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Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons

View ORCID ProfileElectra Brunialti, View ORCID ProfileAlessandro Villa, Marianna Mekhaeil, View ORCID ProfileFederica Mornata, View ORCID ProfileElisabetta Vegeto, View ORCID ProfileAdriana Maggi, View ORCID ProfileDonato A. Di Monte, View ORCID ProfilePaolo Ciana
doi: https://doi.org/10.1101/2021.01.20.427380
Electra Brunialti
1Department of Health Sciences, University of Milan, Milan, Italy
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Alessandro Villa
1Department of Health Sciences, University of Milan, Milan, Italy
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  • For correspondence: paolo.ciana@unimi.it
Marianna Mekhaeil
1Department of Health Sciences, University of Milan, Milan, Italy
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Federica Mornata
2Department of Pharmaceutical Sciences, University of Milan, Italy
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Elisabetta Vegeto
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Adriana Maggi
2Department of Pharmaceutical Sciences, University of Milan, Italy
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Donato A. Di Monte
3German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
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Paolo Ciana
1Department of Health Sciences, University of Milan, Milan, Italy
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  • For correspondence: paolo.ciana@unimi.it
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Abstract

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. In the brain, most of the pathological effects caused by GBA mutations have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Here, we applied the bioluminescence imaging technology, immunohistochemical and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia co-cultures and in cell lines. Our data demonstrate the existence of a novel mechanism by which microglia sustain the antioxidant/detoxifying response mediated by the nuclear factor erythroid 2-related factor 2 in neurons. The central role played by microglia in this neuronal response in vivo was proven by pharmacological depletion of the lineage in the brain, while co-cultures experiments provided insight on the nature of this cell-to-cell communication showing that this mechanism requires a direct microglia-to-neuron contact supported by functional actin structures. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, turn on an anti-inflammatory/repairing pathway and hinder the microglia ability to activate the anti-oxidant/detoxifying response, thus increasing the neuronal susceptibility to neurotoxins.

Altogether, our data suggest that microglial β-glucocerebrosidase inhibition impairs microglia-to-neuron communication increasing the sensitivity of neurons to oxidative or toxic insults, thus providing a possible mechanism for the increased risk of neurodegeneration observed in carriers of GBA mutations.

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In Brief Microglia, through actin-dependent structures, contact neurons and induce a detoxification response by increasing the NFE2L2 signalling pathway. Inhibition of GCase activity by CBE treatment produces a morpho-functional change in microglia cells hampering the neuroprotective microglia-neuron communication thus inducing a phenotype in dopaminergic neurons characterized by increased susceptibility to oxidative stress or toxic insults.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    CBE
    conduritol-B-epoxide
    GCase
    β-glucocerebrosidase
    MPP+
    1-methyl-4-phenylpyridinium
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    NFE2L2
    nuclear factor erythroid 2-related factor 2
    FC
    fold change
    SNpc
    Substantia Nigra pars compacta
    tBHQ
    tert-butylhydroquinone
    Th
    tyrosine hydroxylase
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    Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons
    Electra Brunialti, Alessandro Villa, Marianna Mekhaeil, Federica Mornata, Elisabetta Vegeto, Adriana Maggi, Donato A. Di Monte, Paolo Ciana
    bioRxiv 2021.01.20.427380; doi: https://doi.org/10.1101/2021.01.20.427380
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    Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons
    Electra Brunialti, Alessandro Villa, Marianna Mekhaeil, Federica Mornata, Elisabetta Vegeto, Adriana Maggi, Donato A. Di Monte, Paolo Ciana
    bioRxiv 2021.01.20.427380; doi: https://doi.org/10.1101/2021.01.20.427380

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