Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease

Schonauer, Sophie; Körschen, Heinz G.; Penno, Anke; Rennhack, Andreas; Breiden, Bernadette; Sandhoff, Konrad; Gutbrod, Katharina; Dörmann, Peter; Raju, Diana Nancy; Haberkant, Per; Gerl, Mathias J.; Brügger, Britta; Zigdon, Hila; Vardi, Ayelet; Futerman, Anthony H.; Thiele, Christoph; Wachten, Dagmar

doi:10.1074/jbc.m116.762831

Cited by 24 publications

(28 citation statements)

References 36 publications

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“…However, some of these results have not been validated in subsequent studies, as Schonauer et al. found GBA2 to be downregulated or at control levels in the absence of GCase activity, and that sphingosine itself binds to GBA2 and inhibits the further formation of sphingosine (Schonauer et al., ). These conflicting results indicate that while GBA2 may play a role in GD pathogenesis, its exact role is unclear.…”

Section: Modifiers Of Gaucher Disease: Results Of Candidate Gene Studiesmentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Modifiers Of Gaucher Disease: Results Of Candidate Gene Studiesmentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…In the context of Gaucher disease, a lysosomal storage disorder that develops due to loss of GBA1 activity, we have demonstrated that loss of GBA1 activity results in a concomitant reduction in GBA2 activity (24). However, vice versa, loss of GBA2 activity does not affect GBA1 activity (24).…”

Section: Gba2 Mutations and Locomotor Dysfunctionmentioning

confidence: 94%

“…Loss of GBA2 changes the glycosphingolipid homeostasis (3,4,24). To verify the changes in lipid homeostasis in the brain, in particular in the cerebellum, we analyzed the amount of neutral lipids in the cerebellum of P10 (postnatal day 10) and adult WT and GBA2-KO mice by MS, and we distinguished between sphingoid bases (long-chain bases, C18), ceramides (different chain length, saturated and unsaturated), and hexosylceramides (HexCer, different chain length, saturated and unsaturated).…”

Section: Loss Of Gba2 Activity Diminishes Neurite Outgrowthmentioning

confidence: 99%

“…The assay was performed as described elsewhere (2,24). For AMP-DNM (27), 30 pM was used in the assay in a 25-l sample volume, which, after addition of 5 l of 4-MUG, resulted in a final concentration of 25 pM.…”

Section: ␤-Glucosidase Activity Assaymentioning

confidence: 99%

“…Quantification of lipids using MS was performed as described before (24). Alternatively, sphingolipid analysis was carried out using a QTRAP 6500ϩ LC-MS/MS system (Sciex, Darmstadt) with a Turbo V ion source.…”

Section: Quantification Of Lipids Using Msmentioning

confidence: 99%

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Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations

Woeste

Stern

Raju

et al. 2019

Journal of Biological Chemistry

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The nonlysosomal glucosylceramidase ␤2 (GBA2) catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP), autosomal-recessive cerebellar ataxia (ARCA), and the Marinesco-Sjögren-like syndrome. However, the underlying molecular mechanisms are ill-defined. Here, using biochemistry, immunohistochemistry, structural modeling, and mouse genetics, we demonstrate that all but one of the spastic gait locus #46 (SPG46)-connected mutations cause a loss of GBA2 activity. We demonstrate that GBA2 proteins form oligomeric complexes and that proteinprotein interactions are perturbed by some of these mutations. To study the pathogenesis of GBA2-related HSP and ARCA in vivo, we investigated GBA2-KO mice as a mammalian model system. However, these mice exhibited a high phenotypic variance and did not fully resemble the human phenotype, suggesting that mouse and human GBA2 differ in function. Whereas some GBA2-KO mice displayed a strong locomotor defect, others displayed only mild alterations of the gait pattern and no signs of cerebellar defects. On a cellular level, inhibition of GBA2 activity in isolated cerebellar neurons dramatically affected F-actin dynamics and reduced neurite outgrowth, which has been associated with the development of neurological disorders. Our results shed light on the molecular mechanism underlying the pathogenesis of GBA2-related HSP and ARCA and reveal species-specific differences in GBA2 function in vivo.

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Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown

Aerts

Ferraz

Mirzaian

et al. 2017

Encyclopedia of Life Sciences

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The cellular recycling of glycosphingolipids (GSLs) is mediated by specific lysosomal glycosidases. Inherited deficiencies in these enzymes cause lysosomal storage disorders. Some of the common disorders are Gaucher disease (GD) and Fabry disease (FD) resulting from the defects in lysosomal glucocerebrosidase (GBA) degrading glucosylceramide and α‐galactosidase A (GLA) degrading globotriaosylceramide. Here, GSL accumulation in tissues slows down with age despite ongoing lysosomal turnover of endogenous and endocytosed GSLs. Biochemical adaptations might explain this phenomenon. One crucial adaptation is the deacylation of accumulating GSLs in lysosomes by acid ceramidase. The soluble bases glucosylsphingosine in GD and globotriaosylsphingosine in FD are capable of leaving lysosomes and cells. In the case of GD, a further adaptation involves the cytosol‐faced enzyme GBA2. This enzyme allows extra‐lysosomal degradation of GlcCer while possibly generating glucosylated cholesterol. The beneficial and harmful effects of these adaptations are discussed. Key Concepts Glycosphingolipids (GSLs) are membrane constituents composed of a ceramide with one or more sugars. The simplest GSL is glucosylceramide (GlcCer). Ongoing recycling of GSLs in cells includes lysosomal degradation by the sequential action of glycosidases and acid ceramidase. Deficiency of lysosomal glycosidase leads to lysosomal storage diseases caused by accumulation of the corresponding substrate in lysosomes. The most common glycosphingolipidoses are Gaucher disease (GD) and Fabry disease (FD). GD is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid β‐glucosidase (glucocerebrosidase; GBA) resulting in lysosomal accumulation of GlcCer. FD is an X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A (GLA) resulting in lysosomal accumulation of globotriaosylceramide (Gb3). Accumulation of storage lipids during GBA and GLA tends to slow down with age, likely partly due to poorly appreciated biochemical adaptations. Active conversion of accumulating GlcCer in lysosomes of GBA‐deficient cells is mediated by acid ceramidase, resulting in the formation of water‐soluble glucosylsphingosine (GlcSph). Likewise, globotriaosylsphingosine (lysoGb3) is formed from accumulating in lysosomes of GLA‐deficient cells. Elevated plasma GlcSph and lysoGb3 levels can be sensitively measured LC–MS and may assist in diagnosing and monitoring of the disease and response to treatment in GD and FD patients, respectively. Increased GlcSph level in GD patients acts as an autoantigen, causing ongoing B‐cell proliferation, leading to multiple myeloma. Increased lysoGb3 level in FD patients is thought to cause damage to nociceptive neurons and podocytes, thus contributing to pain and renal failure. In GD, the cytosol‐faced enzyme β‐glucosidase GBA2 allows degradation of GlcCer outside lysosomes. Through transglycosylation, GBA2 may generate glucosylcholesterol and ceramide from GlcCer and cholesterol. The toxic effects of secondary metabolites such as glycosphingoid bases (GlcSph in GD and lysoGb3 in FD) and glucosylated metabolites (GlcChol in GD) warrant further investigations.

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Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease

Cited by 24 publications

References 36 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations

Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown

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