Neuronal activity induces glucosylceramide that is secreted via exosomes for lysosomal degradation in glia

Wang, Liping; Lin, Guang; Zuo, Zhuang; Li, Yarong; Byeon, Seul Kee; Pandey, Akhilesh; Bellen, Hugo J.

doi:10.1126/sciadv.abn3326

Cited by 29 publications

(32 citation statements)

References 89 publications

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“…We previously showed that loss of fly homolog of PLA2G6 leads to an elevation of ceramides including GlcCer ( Lin et al, 2018 ). GlcCer accumulation is also observed in flies that lack the fly homolog of GBA1 ( Wang et al, 2022a ), the gene that causes Gaucher disease ( Sidransky, 2004 ; Wong et al, 2004 ). We performed immunostaining in the cerebellum and midbrain of the Pla2g6 KO/G373R and homozygous Pla2g6 G373R/G373R animals.…”

Section: Resultsmentioning

confidence: 99%

Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

Lin

Tepe

McGrane

et al. 2023

eLife

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Infantile Neuroaxonal Dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived NPCs. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.

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Section: Resultsmentioning

confidence: 99%

Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

Lin

Tepe

McGrane

et al. 2023

eLife

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show abstract

“…We previously showed that loss of fly homolog of PLA2G6 leads to an elevation of ceramides including glucosylceramides (GlcCer) (Lin et al, 2018). GlcCer accumulation is also observed in flies that lack the fly homolog of GBA1 (Wang et al, 2022a), the gene that causes Gaucher disease (Sidransky, 2004; Wong et al, 2004). We performed immunostaining in the cerebellum and midbrain of the PLA2G6 KO/G373R and homozygous PLA2G6 G373R/G373R animals.…”

Section: Resultsmentioning

confidence: 99%

Exploring therapeutic strategies for Infantile Neuronal Axonal Dystrophy (INAD/PARK14)

Lin

Tepe

McGrane

et al. 2022

Preprint

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Infantile Neuroaxonal Dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models the same features are affected and that glucosylceramides are elevated in dopaminergic neurons and Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that ceramides can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived NPCs. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.

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“…It has recently been demonstrated that Gba1b is expressed predominantly within glia, rather than neurons, in the fly brain (Wang et al, 2022). Using the same CRIMIC Gba1b line, in which Gba1b gene expression is disrupted, we co-expressed UAS-mCherry.nls under the Gba1b endogenous promoter (Lee et al, 2018).…”

Section: Resultsmentioning

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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Neuronal activity induces glucosylceramide that is secreted via exosomes for lysosomal degradation in glia

Cited by 29 publications

References 89 publications

Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

Exploring therapeutic strategies for Infantile Neuronal Axonal Dystrophy (INAD/PARK14)

Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

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