TY  - JOUR
AU  - Woeste, Marina A
AU  - Stern, Sina
AU  - Raju, Diana N
AU  - Grahn, Elena
AU  - Dittmann, Dominik
AU  - Gutbrod, Katharina
AU  - Dörmann, Peter
AU  - Hansen, Jan N
AU  - Schonauer, Sophie
AU  - Marx, Carina E
AU  - Hamzeh, Hussein
AU  - Körschen, Heinz G
AU  - Aerts, Johannes M F G
AU  - Bönigk, Wolfgang
AU  - Endepols, Heike
AU  - Sandhoff, Roger
AU  - Geyer, Matthias
AU  - Berger, Thomas K
AU  - Bradke, Frank
AU  - Wachten, Dagmar
TI  - Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.
JO  - The journal of biological chemistry
VL  - 294
IS  - 11
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-06906
SP  - 3853-3871
PY  - 2019
AB  - 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.
KW  - Glucosylceramidase
KW  - Animals
KW  - Biocatalysis
KW  - Cerebellar Ataxia: genetics
KW  - Cerebellar Ataxia: metabolism
KW  - Humans
KW  - Locomotion: genetics
KW  - Loss of Function Mutation
KW  - Mice
KW  - Mice, Knockout
KW  - Spastic Paraplegia, Hereditary: genetics
KW  - Spastic Paraplegia, Hereditary: metabolism
KW  - Species Specificity
KW  - beta-Glucosidase: antagonists & inhibitors
KW  - beta-Glucosidase: deficiency
KW  - beta-Glucosidase: genetics
KW  - beta-Glucosidase: metabolism
KW  - beta-Glucosidase (NLM Chemicals)
KW  - beta-glucosidase 2, mouse (NLM Chemicals)
KW  - GBA2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30662006
C2  - pmc:PMC6422076
DO  - DOI:10.1074/jbc.RA118.006311
UR  - https://pub.dzne.de/record/140584
ER  -