ImmunoSensation - the immune sensory system

J Biol Chem. 2019 Jan 20.

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

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

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