Journal Article

DZNE-2020-06906

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.

Woeste, M. A. ; Stern, S.DZNE* ; Raju, D. N. ; Grahn, E. ; Dittmann, D. ; Gutbrod, K. ; Dörmann, P. ; Hansen, J. N. ; Schonauer, S. ; Marx, C. E. ; Hamzeh, H. ; Körschen, H. G. ; Aerts, J. M. F. G. ; Bönigk, W. ; Endepols, H. ; Sandhoff, R. ; Geyer, M. ; Berger, T. K. ; Bradke, F.DZNE* ; Wachten, D. (Corresponding author)

2019
Soc.60645 Bethesda, Md.

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Please use a persistent id in citations: doi:10.1074/jbc.RA118.006311

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.

Keyword(s): Glucosylceramidase (MeSH) ; Animals (MeSH) ; Biocatalysis (MeSH) ; Cerebellar Ataxia: genetics (MeSH) ; Cerebellar Ataxia: metabolism (MeSH) ; Humans (MeSH) ; Locomotion: genetics (MeSH) ; Loss of Function Mutation (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Spastic Paraplegia, Hereditary: genetics (MeSH) ; Spastic Paraplegia, Hereditary: metabolism (MeSH) ; Species Specificity (MeSH) ; beta-Glucosidase: antagonists & inhibitors (MeSH) ; beta-Glucosidase: deficiency (MeSH) ; beta-Glucosidase: genetics (MeSH) ; beta-Glucosidase: metabolism (MeSH) ; beta-Glucosidase ; beta-glucosidase 2, mouse ; GBA2 protein, human

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Contributing Institute(s):

1. Axon Growth and Regeneration (AG Bradke)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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