Lysosomal storage and impaired autophagy lead to inflammasome activation in
            <scp>G</scp>
            aucher macrophages

Aflaki, Elma; Moaven, Nima; Borger, Daniel K.; Lopez, Grisel; Westbroek, Wendy; Chae, Jae Jin; Marugán, Juan; Patnaik, Samarjit; Maniwang, Emerson; Gonzalez, Ashley N.; Sidransky, Ellen

doi:10.1111/acel.12409

Cited by 132 publications

(110 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lysosomal integrity is necessary for normal functioning of the autophagy degradation machinery (Xu and Ren, 2015), and accordingly we observed autophagy dysfunction in dGBA1b Ϫ/Ϫ brains, with accumulation of the autophagolysosomal protein Atg8/LC3. Thus, we demonstrate autophagy defects at the level of the autophagic machinery in vivo in a GD Drosophila model, following on from in vitro studies in GD macrophages and iPSCs showing impaired autophagy (Awad et al, 2015;Aflaki et al, 2016;Fernandes et al, 2016).…”

Section: Discussionsupporting

confidence: 53%

“…In keeping with the importance of lysosomes in the autophagy pathway, it was recently shown in macrophages and induced pluripotent stem cell (iPSC)-derived neuronal cells from GD patients that autophagy is impaired (Awad et al, 2015;Aflaki et al, 2016). Furthermore, this defect in autophagy was shown to trigger inflammasome activation and the production of inflammatory cytokines (Aflaki et al, 2016).…”

Section: Introductionmentioning

confidence: 92%

“…Furthermore, this defect in autophagy was shown to trigger inflammasome activation and the production of inflammatory cytokines (Aflaki et al, 2016). Moreover, Osellame et al (2013) demonstrated that there is accumulation of dysfunctional and fragmented mitochondria in a neuronopathic mouse model of GD, thought to be secondary to autophagic and proteasomal defects.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

et al. 2016

View full text Add to dashboard Cite

Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Thus, CGD was defined as a potentially lethal combination of immunodeficiency and excess inflammation (67), most likely due to cell-autonomous stress responses. Likewise, evidence is accumulating for a role of stress and inflammation in the pathogenesis of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (68). Monocyte/macrophages from these patients display increased secretion of IL-1β that depends on increased inflammasome activation, in turn due to the impaired autophagy secondary to the lysosomal enzyme deficiency (68).…”

Section: Cell-autonomous Proteotoxic Stress In Monocytes Increases Ilmentioning

confidence: 99%

“…Likewise, evidence is accumulating for a role of stress and inflammation in the pathogenesis of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (68). Monocyte/macrophages from these patients display increased secretion of IL-1β that depends on increased inflammasome activation, in turn due to the impaired autophagy secondary to the lysosomal enzyme deficiency (68). A further example is mucopolysaccharidosis type I, where, in innate immune cells, stress induced by lysosomal storage defects can upregulate immunity-related genes.…”

Section: Cell-autonomous Proteotoxic Stress In Monocytes Increases Ilmentioning

confidence: 99%

Dysregulated IL-1β Secretion in Autoinflammatory Diseases: A Matter of Stress?

et al. 2017

View full text Add to dashboard Cite

Infectious and sterile inflammation is induced by activation of innate immune cells. Triggering of toll-like receptors by pathogen-associated molecular pattern or damage-associated molecular pattern (PAMP or DAMP) molecules generates reactive oxygen species that in turn induce production and activation of pro-inflammatory cytokines such as IL-1β. Recent evidence indicates that cell stress due to common events, like starvation, enhanced metabolic demand, cold or heat, not only potentiates inflammation but may also directly trigger it in the absence of PAMPs or DAMPs. Stress-mediated inflammation is also a common feature of many hereditary disorders, due to the proteotoxic effects of mutant proteins. We propose that harmful mutant proteins can induce dysregulated IL-1β production and inflammation through different pathways depending on the cell type involved. When expressed in professional inflammatory cells, stress induced by the mutant protein activates in a cell-autonomous way the onset of inflammation and mediates its aberrant development, resulting in the explosive responses that hallmark autoinflammatory diseases. When expressed in non-immune cells, the mutant protein may cause the release of transcellular stress signals that trigger and propagate inflammation.

show abstract

Long‐term follow‐up of a patient with neonatal form of Gaucher disease

Gragnaniello

Cazzorla

Gueraldi

et al. 2023

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Gaucher disease is the most common of the lysosomal storage diseases. It presents a wide phenotypic continuum, in which one may identify the classically described phenotypes, including type 1 form with visceral involvement, type 2 acute neuropathic early‐infantile form, and type 3 subacute neuronopathic form. At the most severe end there is the perinatal form with onset in utero or during the neonatal period. The very few reported cases of neonatal onset Gaucher disease presented high and early mortality, due to neurological or visceral involvement, including liver failure. We report our experience treating a patient with the neonatal form of Gaucher disease who presented at birth with thrombocytopenia, hepatosplenomegaly and cholestasis. Despite early enzyme replacement therapy, liver disease was progressive. Liver biopsy showed hepatocellular giant‐cell transformation, a nonspecific finding consistent with inflammation. The lack of response to enzyme replacement therapy and the microscopic findings suggested that mechanisms apart from substrate accumulation and Gaucher cells may play a role in the hepatic pathogenesis in Gaucher disease. An attempt to use corticosteroids at the age of 3 months resulted in a dramatic improvement in liver function and resulted in long‐term survival. The patient is alive and 2 years old at this writing. Our case suggests that inflammatory processes may be important in the early pathogenesis of Gaucher disease and that early use of corticosteroids may open the way to a new therapeutic approach.

show abstract

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Cited by 132 publications

References 53 publications

ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

Dysregulated IL-1β Secretion in Autoinflammatory Diseases: A Matter of Stress?

Long‐term follow‐up of a patient with neonatal form of Gaucher disease

Contact Info

Product

Resources

About