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

著者 Woeste MA , Stern S , Raju DN , Grahn E , Dittmann D , Gutbrod K , Dörmann P , Hansen JN , Schonauer S , Marx CE , Hamzeh H , Körschen HG , Aerts JMFG , Bōnigk W , Endepols H , Sandhoff R , Geyer M , Berger TK , Bradke F , Wachten D
J Biol Chem.2019 Jan 20 ; ():.
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The non-lysosomal glucosylceramidase (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 mice 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.
PMID: 30662006 [PubMed - as supplied by publisher]
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