The Enigmatic Role of GBA2 in Controlling Locomotor Function

Woeste, Marina A; Wachten, Dagmar

doi:10.3389/fnmol.2017.00386

Cited by 22 publications

(26 citation statements)

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“…Ceramides are further deacetylated to sphingosines that can be broken down or recycled for sphingolipid synthesis by the salvage pathway [25]. Non-lysosomal pathways of degradation also exist and for instance glucosylceramides can be degraded not only by the lysosomal glucocerebrosidase, but also by the non-lysosomal glucocerebrosidase (encoded by the GBA2 gene) and the cytosolic Klothorelated glucocerebrosidase (encoded by the GBA3 gene) [26][27][28][29][30][31]. Fig.…”

Section: Metabolism Of Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and neuroinflammation in Parkinson’s disease

Bélarbi¹,

Cuvelier²,

Bonte³

et al. 2020

Mol Neurodegeneration

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Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson’s disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson’s disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson’s disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson’s disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson’s disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.

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Section: Metabolism Of Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and neuroinflammation in Parkinson’s disease

Bélarbi¹,

Cuvelier²,

Bonte³

et al. 2020

Mol Neurodegeneration

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“…The mutations found in the GBA2 gene are either missense mutations, exchanging one amino acid for another, or nonsense mutations, leading to a premature transcriptional stop and thereby protein truncation (17). Most of the missense mutations are located in the C-terminal catalytic domain, and those leading to protein truncation lack the catalytic domain (17). The majority of SPG46 patients carry homozygous mutations and only a few are compound heterozygous mutant carriers (Table 1) (17).…”

mentioning

confidence: 99%

“…Most of the missense mutations are located in the C-terminal catalytic domain, and those leading to protein truncation lack the catalytic domain (17). The majority of SPG46 patients carry homozygous mutations and only a few are compound heterozygous mutant carriers (Table 1) (17). Some of the mutations have been analyzed in vitro and failed to produce a ␤-glucosidase activity (18).…”

mentioning

confidence: 99%

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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“…Altogether, targeting GBA2 does not have the same consequences in humans as in mice; humans depend to a much greater extent on GBA2 for proper development of the central nervous system and motor control in arms and legs. This species difference is not understood at present [29]. Further, it may appear paradoxical that, in humans, different ways of targeting GBA2 have different consequences, as the GBA2 inhibitor miglustat is well tolerated while mutations in the GBA2 gene result in a range of neurological and non-neurological symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…The genetic abnormalities identified in the human GBA2 gene include missense, nonsense, splice site, and frameshift mutations ( Fig 1A), most of which are present in a homozygous fashion. It is unclear how the mutations in the GBA2 gene give rise to the range of disease manifestations seen in SPG46 and MSS patients [29]. To obtain insights into the physiological role of GBA2 and into the etiology of SPG46 and MSS, we previously modeled ten SPG46-associated GBA2 mutations in the cDNA coding for human GBA2, and found that single amino acid-substituted and C-terminally truncated forms of GBA2 failed to cleave its substrate [22].…”

Section: Introductionmentioning

confidence: 99%

Truncated mutants of beta-glucosidase 2 (GBA2) are localized in the mitochondrial matrix and cause mitochondrial fragmentation

2020

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The enzyme β-glucosidase 2 (GBA2) is clinically relevant because it is targeted by the drug miglustat (Zavesca ®) and because it is involved in inherited diseases. Mutations in the GBA2 gene are associated with two neurological diseases on the ataxia-spasticity spectrum, hereditary spastic paraplegia 46 (SPG46) and Marinesco-Sjö gren-like syndrome (MSS). To establish how GBA2 mutations give rise to neurological pathology, we have begun to investigate mutant forms of GBA2 encoded by disease-associated GBA2 alleles. Previously, we found that five GBA2 missense mutants and five C-terminally truncated mutants lacked enzyme activity. Here we have examined the cellular locations of wild-type (WT) and mutant forms of GBA2 by confocal and electron microscopy, using transfected cells. Similar to GBA2-WT, the D594H and M510Vfs*17 GBA2 mutants were located at the plasma membrane, whereas the C-terminally truncated mutants terminating after amino acids 233 and 339 (GBA2-233 and-339) were present in the mitochondrial matrix, induced mitochondrial fragmentation and loss of mitochondrial transmembrane potential. Deletional mutagenesis indicated that residues 161-200 are critical for the mitochondrial fragmentation of GBA2-233 and-339. Considering that the mitochondrial fragmentation induced by GBA2-233 and-339 is consistently accompanied by their localization to the mitochondrial matrix, our deletional analysis raises the possibility that that GBA2 residues 161-200 harbor an internal targeting sequence for transport to the mitochondrial matrix. Altogether, our work provides new insights into the behaviour of GBA2-WT and disease-associated forms of GBA2.

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The Enigmatic Role of GBA2 in Controlling Locomotor Function

Cited by 22 publications

References 58 publications

Glycosphingolipids and neuroinflammation in Parkinson’s disease

Glycosphingolipids and neuroinflammation in Parkinson’s disease

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

Truncated mutants of beta-glucosidase 2 (GBA2) are localized in the mitochondrial matrix and cause mitochondrial fragmentation

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