ArticlePLoS genetics2023
Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease.
Article in PLoS genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 20 citations in OpenAlex.
- Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.Neural regeneration research · 2026Article
- The underexplored mycobiome: insights from Drosophila into human health and disease.Antonie van Leeuwenhoek · 2026Review
- Neuropsychiatric disorders in pulmonary fibrosis: from brain network alterations to inflammatory mechanisms and therapeutic implications.Journal of neuroinflammation · 2026Review
- Association Between Blood-Brain Barrier Disruption and Gut Microbiota Dysbiosis in Parkinson's Disease.Cellular and molecular neurobiology · 2026Review
- Parkinson's-Linked LRRK2 and GBA1 Mutations Modulate the Peripheral Immune Response to Pseudomonas aeruginosa.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- The role of gut dysbiosis in Parkinson's disease: pathophysiology, epidemiology, and emerging therapeutic strategies.Metabolic brain disease · 2026Review
- Refining Mouse Models of Gaucher Disease: Advancing Mechanistic Insights, Biomarker Discovery, and Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Unseen toxins: Exploring the human health consequences of micro and nanoplastics.Toxicology reports · 2025Review
- Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.Biochemistry and biophysics reports · 2025Article
- Exploring the relationship betweenFrontiers in neuroscience · 2025Article
- Ceramide lowering rescues respiratory defects in a Drosophila model of acid sphingomyelinase deficiency.Human molecular genetics · 2024Article
- Atypical gut microbiota composition in a mouse model of developmental stuttering.Scientific reports · 2024Article
- Does glial lipid dysregulation alter sleep in Alzheimer's and Parkinson's disease?Trends in molecular medicine · 2024Review
- Functional Analysis of HumanCells · 2024Article
- Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Autophagic dysregulation triggers innate immune activation in glucocerebrosidase deficiency.Autophagy reports · 2024Article
- Microbiota gut-brain axis: implications for pediatric-onset leukodystrophies.Frontiers in nutrition · 2024Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.