The Uncovered Function of the Drosophila GBA1a-Encoded Protein

Cabasso, Or; Paul, Surojit; Maor, Gali; Pasmanik‐Chor, Metsada; Kallemeijn, Wouter W.; Aerts, Johannes M. F. G.; Horowitz, Mia

doi:10.3390/cells10030630

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…This is in keeping with a previous study in flies harbouring insertions of minos elements in the two Gba1 genes, resulting in the production of truncated mutant GCase proteins. These flies displayed up-regulation of IMD and Toll pathway genes in the head and body [ 20 , 55 ]. Our results thus confirm that complete loss of Gba1b gene activity is associated with strong innate immune activation, including the JAK-STAT stress response.…”

Section: Discussionmentioning

confidence: 99%

Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease

Atilano,

Hull,

Romila

et al. 2023

PLoS Genet

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Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson’s disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread NF-kB signalling activation, including gut inflammation, and brain glial activation. We also demonstrate intestinal autophagic defects, gut dysfunction, and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, partially ameliorates lifespan, locomotor and immune phenotypes. Moreover, we show that modulation of the immune deficiency (IMD) pathway is detrimental to the survival of Gba1 deficient flies. We also reveal that direct stimulation of autophagy by rapamycin treatment achieves similar benefits to germ-free conditions independent of gut bacterial load. Consistent with this, we show that pharmacologically blocking autophagosomal-lysosomal fusion, mimicking the autophagy defects of Gba1 depleted cells, is sufficient to stimulate intestinal immune activation. Overall, our data elucidate a mechanism whereby an altered microbiome, coupled with defects in autophagy, drive chronic activation of NF-kB signaling in a Gba1 loss-of-function model. It also highlights that elimination of the microbiota or stimulation of autophagy to remove immune mediators, rather than prolonged immunosuppression, may represent effective therapeutic avenues for GBA1-associated disorders.

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Section: Discussionmentioning

confidence: 99%

Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease

Atilano,

Hull,

Romila

et al. 2023

PLoS Genet

View full text Add to dashboard Cite

show abstract

“…This is in keeping with a previous study in flies harbouring insertions of minos elements in the two Gba1 genes, resulting in the production of truncated mutant GCase proteins. These flies displayed up-regulation of IMD and Toll pathway genes in the head and body (Cabasso et al, 2019, Cabasso et al, 2021). Our results thus confirm that complete loss of Gba1b gene activity is associated with strong innate immune activation, including the JAK-STAT stress response.…”

Section: Discussionmentioning

confidence: 99%

Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Atilano

Hull

Romila

et al. 2022

Preprint

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Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest genetic risk factor for Parkinson disease (PD). Communication between gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread innate immune up-regulation, including gut inflammation and brain glial activation. We also demonstrate gut dysfunction in flies lacking Gba1b, with increased intestinal transit time, gut barrier permeability and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, can partially ameliorate lifespan, locomotor and some neuropathological phenotypes. Lastly, direct stimulation of autophagy by rapamycin treatment achieves similar beneficial effects. Overall, our data reveal that the gut microbiome drives systemic immune activation in Gba1b knockout flies and that reducing innate immune response activation either by eliminating the microbiota or clearance of immunogens by autophagy may represent potential therapeutic avenues for GBA1-associated neurodegenerative disease.

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“…The same is true fo of the six amino acids that stabilize the substrate in the active pocket of GCase ( W179, F246, Y313, W381 in human GCase, F154, W206, F272, Y339, W408, in bo GBA1-encoded proteins, respectively) [130]. Interestingly, the Gba1a-encoded protein has no GCase-like activity or any oth sosomal enzyme activity [131]. It encodes a protein, which modulates developmentlated apoptosis [131,132].…”

Section: Fly Modelsmentioning

confidence: 94%

“…GBA1-encoded proteins, respectively) [130]. Interestingly, the Gba1a-encoded protein has no GCase-like activity or any other lysosomal enzyme activity [131]. It encodes a protein, which modulates development-regulated apoptosis [131,132].…”

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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The Uncovered Function of the Drosophila GBA1a-Encoded Protein

Cited by 8 publications

References 47 publications

Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease

Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease

Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Animal Models for the Study of Gaucher Disease

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