Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46)

Sultana, Saki; Reichbauer, Jennifer; Schüle, Rebecca; Mochel, Fanny; Synofzik, Matthis; Spoel, Aarnoud C. van der

doi:10.1016/j.bbrc.2015.07.112

Cited by 37 publications

(45 citation statements)

References 23 publications

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“…Gaucher disease is caused by homozygous mutations in GBA1, which are an important risk factor for Parkinson disease 59 , and mutations in the non-lysosomal GBA2 have been linked to hereditary spastic paraplegia 60 and spastic ataxia 61 .The covalent binding of CBE to GCases may easily lead to full inhibition of total GCase activity if given in high enough dose, as shown in our in vitro assay. CBE has been used to induce a chemical model of Gaucher disease in neonatal mice 26 .…”

Section: Discussionmentioning

confidence: 65%

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Henriques

Huebecker

Blasco

et al. 2017

Sci Rep

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Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

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Section: Discussionmentioning

confidence: 65%

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Henriques

Huebecker

Blasco

et al. 2017

Sci Rep

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“…Some exemplary clusters of shared or interacting pathways underlying ASS diseases are: Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ). Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 . Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

“…Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 .…”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

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“…The physiological function of the highly conserved enzyme is enigmatic. The inhibition of GBA2 in Gaucher disease and Niemann-Pick type C patients treated with N-butyldeoxynojirimycin (NB-DNJ; miglustat) seems not to cause major complications, whereas some individuals with inherited GBA2 deficiency develop spastic paraplegia and cerebellar ataxia (21)(22)(23)(24). Mice lacking GBA2 develop normally and show no overt abnormality, except for incidences of male infertility (61).…”

Section: Glycosylceramidases Of Family Gh116mentioning

confidence: 99%

“…Moreover, deficiency of this enzyme has been implicated in the etiology of Parkinson disease (18,19). Inherited deficiency of GBA2 results in spastic paraplegia and cerebellar ataxia (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

Bdira

Artola

Overkleeft

et al. 2018

Journal of Lipid Research

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Glycoconjugates play essential roles in diverse biological processes and abnormalities and have been linked to multiple pathologies. The staggering structural diversity of glycoconjugates stems from the almost infinite possible combinations by which multiple monosaccharide building blocks may be linked with each other (1). For instance, 1,056 unique trisaccharides can be formed just from 3 different monosaccharides. Polysaccharides are very stable compounds: their spontaneous hydrolysis takes place at a rate of 10 15 s 1 , corresponding to a half-life of 4.7 million years (2). To allow for the efficient metabolism of glycoconjugates, enzymes have evolved as specialized catalysts. In most organisms, an estimated 1% to 3% of the genes encode carbohydrate-active enzymes (3). Among these are glycoside hydrolases (GHs) that can enhance the rate of hydrolysis of specific carbohydrate glycosidic bonds in glycoconjugates more than 10 17 times (2). These GH enzymes show marked specificity regarding number, position, and configuration of the hydroxyl groups in their substrate sugar. They are widely applied in biotechnology, for example, in biofuel production, paper pulp bleaching, and the food industry (4, 5). Likewise, specific GH inhibitors are extensively used as agrochemicals and therapeutic agents (6-8). Abnormalities in GHs underlie metabolic disorders in humans, for instance, inherited lysosomal storage disorders and lactose intolerance (9, 10). GH enzymes differ in substrate specificity, mode of enzymatic attack Abstract Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific -glycosidic bond in glycoconjugate substrates; -glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (/) 8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (/) 6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic -glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the function...

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Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46)

Cited by 37 publications

References 23 publications

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

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