Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Atilano, Magda L.; Hull, Alexander; Romila, Catalina-Andreea; Adams, Mirjam Lisette; Wildfire, Jacob; Ureña, Enric; Dyson, Miranda C.; Ivan-Castillo-Quan, Jorge; Partridge, Linda; Kinghorn, Kerri J.

doi:10.1101/2022.12.15.520449

Cited by 2 publications

(3 citation statements)

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“…Alternatively, GlcCer accumulation in macrophages could cause hyperreactivity to normal immune stimuli, as previously reported in macrophages from PD patients with GBA mutations [15]. Atilano et al [26] partially addressed this possibility by raising GCase-deficient flies in germ-free conditions. The improvements in lifespan and climbing after this intervention, however, were modest compared to those seen when we restored GCase activity in activated macrophages.…”

Section: Discussionmentioning

confidence: 98%

“…The major humoral immune pathways in mammals, including Toll, NF-κB/Imd, and JAK/STAT, are conserved in Drosophila [21, 22], and Drosophila blood cells (hemocytes) are a well-validated model for macrophages and other human myeloid immune cells [23, 24]. In addition, Drosophila studies have shown the same association between GCase deficiency and immune system activation that is seen in mammals [25, 26]. We therefore used the Gba1b mutant to determine which components of the immune system contribute to the neuropathology associated with GCase deficiency.…”

Section: Introductionmentioning

confidence: 99%

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Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Vincow,

Thomas,

Milstein

et al. 2023

Preprint

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Mutations inGBA(glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson’s disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred byGBAmutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in aDrosophilamodel of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressingGba1bin activated macrophages suppressed head protein aggregation inGba1bmutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also amelioratedGba1bmutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.Author SummaryMutations in the geneGBAare the largest risk factor for developing Parkinson’s disease and Lewy body dementia, diseases in which important brain cells die. We know that the immune system can be involved in these diseases, and thatGBAmutations cause immune changes. We did experiments to learn how the immune system changes could make brain cells more likely to die. Using a fruit fly that was missing the fly version ofGBA, we found out that inappropriately activated immune cells, but not secreted immune proteins, were important in the development of brain problems. We also learned that the abnormal activation was triggered by the lack ofGBAfunction in the immune cells, not by signals from the brain or other parts of the body. We would like to find out next whether the immune cells get inside the brain or cause harm from a distance. What we learned matters because it could help us prevent or cure brain diseases associated withGBAmutations. Treating the abnormal activation of immune cells in people with these mutations might help prevent damage to the brain.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Vincow,

Thomas,

Milstein

et al. 2023

Preprint

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“…Both single and double KO flies presented lysosomal defects, progressive age-dependent locomotor deficits, a seven-fold increase in the amount of C16:0 GlcCer in comparison to age-matched controls, autophagic deficits in their brains, synaptic loss and neurodegeneration. Recently, Atilano et al used this Gba1b KO model to study immune and gut pathologies and noticed that these flies had upregulated inflammation, gut dysfunction (increased intestinal transit time, gut barrier permeability, and microbiome dysbiosis), and glial activation in the brain [135].…”

Section: Ko Drosophila Modelsmentioning

confidence: 99%

Animal Models for the Study of Gaucher Disease

Cabasso,

Kuppuramalingam,

Lelieveld

et al. 2023

IJMS

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In Gaucher disease (GD), a relatively common sphingolipidosis, the mutant lysosomal enzyme acid β-glucocerebrosidase (GCase), encoded by the GBA1 gene, fails to properly hydrolyze the sphingolipid glucosylceramide (GlcCer) in lysosomes, particularly of tissue macrophages. As a result, GlcCer accumulates, which, to a certain extent, is converted to its deacylated form, glucosylsphingosine (GlcSph), by lysosomal acid ceramidase. The inability of mutant GCase to degrade GlcSph further promotes its accumulation. The amount of mutant GCase in lysosomes depends on the amount of mutant ER enzyme that shuttles to them. In the case of many mutant GCase forms, the enzyme is largely misfolded in the ER. Only a fraction correctly folds and is subsequently trafficked to the lysosomes, while the rest of the misfolded mutant GCase protein undergoes ER-associated degradation (ERAD). The retention of misfolded mutant GCase in the ER induces ER stress, which evokes a stress response known as the unfolded protein response (UPR). GD is remarkably heterogeneous in clinical manifestation, including the variant without CNS involvement (type 1), and acute and subacute neuronopathic variants (types 2 and 3). The present review discusses animal models developed to study the molecular and cellular mechanisms underlying GD.

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Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Cited by 2 publications

References 82 publications

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Animal Models for the Study of Gaucher Disease

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