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000140584 0247_ $$2doi$$a10.1074/jbc.RA118.006311
000140584 0247_ $$2pmid$$apmid:30662006
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000140584 0247_ $$2ISSN$$a0021-9258
000140584 0247_ $$2ISSN$$a1067-8816
000140584 0247_ $$2ISSN$$a1083-351X
000140584 0247_ $$2altmetric$$aaltmetric:55338395
000140584 037__ $$aDZNE-2020-06906
000140584 041__ $$aEnglish
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000140584 1001_ $$aWoeste, Marina A$$b0
000140584 245__ $$aSpecies-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.
000140584 260__ $$aBethesda, Md.$$bSoc.60645$$c2019
000140584 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2019-01-20
000140584 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2019-03-15
000140584 3367_ $$2DRIVER$$aarticle
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000140584 3367_ $$2BibTeX$$aARTICLE
000140584 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000140584 3367_ $$00$$2EndNote$$aJournal Article
000140584 520__ $$aThe nonlysosomal glucosylceramidase β2 (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 protein-protein 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.
000140584 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x0
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000140584 650_7 $$0EC 3.2.1.21$$2NLM Chemicals$$abeta-Glucosidase
000140584 650_7 $$0EC 3.2.1.21$$2NLM Chemicals$$abeta-glucosidase 2, mouse
000140584 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGBA2 protein, human
000140584 650_2 $$2MeSH$$aGlucosylceramidase
000140584 650_2 $$2MeSH$$aAnimals
000140584 650_2 $$2MeSH$$aBiocatalysis
000140584 650_2 $$2MeSH$$aCerebellar Ataxia: genetics
000140584 650_2 $$2MeSH$$aCerebellar Ataxia: metabolism
000140584 650_2 $$2MeSH$$aHumans
000140584 650_2 $$2MeSH$$aLocomotion: genetics
000140584 650_2 $$2MeSH$$aLoss of Function Mutation
000140584 650_2 $$2MeSH$$aMice
000140584 650_2 $$2MeSH$$aMice, Knockout
000140584 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: genetics
000140584 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: metabolism
000140584 650_2 $$2MeSH$$aSpecies Specificity
000140584 650_2 $$2MeSH$$abeta-Glucosidase: antagonists & inhibitors
000140584 650_2 $$2MeSH$$abeta-Glucosidase: deficiency
000140584 650_2 $$2MeSH$$abeta-Glucosidase: genetics
000140584 650_2 $$2MeSH$$abeta-Glucosidase: metabolism
000140584 7001_ $$0P:(DE-2719)2810277$$aStern, Sina$$b1$$udzne
000140584 7001_ $$aRaju, Diana N$$b2
000140584 7001_ $$aGrahn, Elena$$b3
000140584 7001_ $$aDittmann, Dominik$$b4
000140584 7001_ $$aGutbrod, Katharina$$b5
000140584 7001_ $$aDörmann, Peter$$b6
000140584 7001_ $$0P:(DE-HGF)0$$aHansen, Jan N$$b7
000140584 7001_ $$aSchonauer, Sophie$$b8
000140584 7001_ $$aMarx, Carina E$$b9
000140584 7001_ $$aHamzeh, Hussein$$b10
000140584 7001_ $$aKörschen, Heinz G$$b11
000140584 7001_ $$aAerts, Johannes M F G$$b12
000140584 7001_ $$aBönigk, Wolfgang$$b13
000140584 7001_ $$aEndepols, Heike$$b14
000140584 7001_ $$aSandhoff, Roger$$b15
000140584 7001_ $$aGeyer, Matthias$$b16
000140584 7001_ $$aBerger, Thomas K$$b17
000140584 7001_ $$0P:(DE-2719)2810270$$aBradke, Frank$$b18$$udzne
000140584 7001_ $$0P:(DE-HGF)0$$aWachten, Dagmar$$b19$$eCorresponding author
000140584 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.ra118.006311$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2019-01-20$$n11$$p3853-3871$$tJournal of Biological Chemistry$$v294$$x0021-9258$$y2019
000140584 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.RA118.006311$$gVol. 294, no. 11, p. 3853 - 3871$$n11$$p3853-3871$$q294:11<3853 - 3871$$tThe journal of biological chemistry$$v294$$x0021-9258$$y2019
000140584 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422076
000140584 909CO $$ooai:pub.dzne.de:140584$$pVDB
000140584 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810277$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE
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000140584 9131_ $$0G:(DE-HGF)POF3-341$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$aDE-HGF$$bForschungsbereich Gesundheit$$lErkrankungen des Nervensystems$$vMolecular Signaling$$x0
000140584 9141_ $$y2019
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