%0 Journal Article
%A Woeste, Marina A
%A Stern, Sina
%A Raju, Diana N
%A Grahn, Elena
%A Dittmann, Dominik
%A Gutbrod, Katharina
%A Dörmann, Peter
%A Hansen, Jan N
%A Schonauer, Sophie
%A Marx, Carina E
%A Hamzeh, Hussein
%A Körschen, Heinz G
%A Aerts, Johannes M F G
%A Bönigk, Wolfgang
%A Endepols, Heike
%A Sandhoff, Roger
%A Geyer, Matthias
%A Berger, Thomas K
%A Bradke, Frank
%A Wachten, Dagmar
%T Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.
%J The journal of biological chemistry
%V 294
%N 11
%@ 0021-9258
%C Bethesda, Md.
%I Soc.60645
%M DZNE-2020-06906
%P 3853-3871
%D 2019
%X The 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.
%K Glucosylceramidase
%K Animals
%K Biocatalysis
%K Cerebellar Ataxia: genetics
%K Cerebellar Ataxia: metabolism
%K Humans
%K Locomotion: genetics
%K Loss of Function Mutation
%K Mice
%K Mice, Knockout
%K Spastic Paraplegia, Hereditary: genetics
%K Spastic Paraplegia, Hereditary: metabolism
%K Species Specificity
%K beta-Glucosidase: antagonists & inhibitors
%K beta-Glucosidase: deficiency
%K beta-Glucosidase: genetics
%K beta-Glucosidase: metabolism
%K beta-Glucosidase (NLM Chemicals)
%K beta-glucosidase 2, mouse (NLM Chemicals)
%K GBA2 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30662006
%2 pmc:PMC6422076
%R 10.1074/jbc.RA118.006311
%U https://pub.dzne.de/record/140584