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

Woeste, Marina A.; Stern, Sina; Raju, Diana N.; Grahn, Elena; Dittmann, Dominik; Gutbrod, Katharina; Doermann, Peter; Hansen, Jan N.; Schonauer, Sophie; Marx, Carina E.; Hamzeh, Hussein; Koerschen, Heinz G.; Aerts, Johannes M. F. G.; Boenigk, Wolfgang; Endepols, Heike; Sandhoff, Roger; Geyer, Matthias; Berger, Thomas Klaus; Bradke, Frank; Wachten, Dagmar

doi:10.1074/jbc.RA118.006311

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

MPS-Authors

Woeste, Marina A.
Max Planck Research Group Molecular Physiology, Center of Advanced European Studies and Research (caesar), Max Planck Society;
External Organizations;

Grahn, Elena
Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Schonauer, Sophie
Max Planck Research Group Molecular Physiology, Center of Advanced European Studies and Research (caesar), Max Planck Society;
External Organizations;

Marx, Carina E.
Max Planck Research Group Molecular Physiology, Center of Advanced European Studies and Research (caesar), Max Planck Society;
External Organizations;

Hamzeh, Hussein
Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Koerschen, Heinz G.
Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Boenigk, Wolfgang
Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Geyer, Matthias
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Berger, Thomas Klaus
Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), Max Planck Society;

/persons/resource/persons182737

Wachten, Dagmar
Max Planck Research Group Molecular Physiology, Center of Advanced European Studies and Research (caesar), Max Planck Society;
External Organizations;

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http://www.jbc.org/content/294/11/3853.full?sid=425ad20a-4852-4d8a-bde9-3800d96633d6
(Abstract)

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Citation

Woeste, M. A., Stern, S., Raju, D. N., Grahn, E., Dittmann, D., Gutbrod, K., et al. (2019). Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. The Journal of Biological Chemistry, 294(11), 3853-3871. doi:10.1074/jbc.RA118.006311.

Cite as: https://hdl.handle.net/21.11116/0000-0003-E7F9-0

Abstract

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.