Molecular Bases of Disease
Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutationsGBA2 mutations and locomotor dysfunction

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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.

glycerosphingolipid
ataxia
neuroscience
neurite outgrowth
cytoskeleton
actin cytoskeleton
β-glucosidases
cerebellar ataxia
GBA2
glucosylceramide

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This work was supported by Deutsche Forschungsgemeinschaft (DFG) Grants SFB645 (to D. W. and P. D.), TRR83 (to D. W.), SPP1926 (to D. W.), SPP1726 (to D. W.), and FOR2743 (to D. W.), the Fritz-Thyssen Foundation (to D. W.), and the Boehringer Ingelheim Stiftung (to D. W.). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Figs. S1–S6 and Table S1.

1

Both authors contributed equally to this work.

2

Present address: Institute of Pharmaceutical Microbiology, University of Bonn, 53115 Bonn, Germany.

3

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – EXC2151 – 390873048.