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

The nonlysosomal glucosylceramidase ß2 (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.

The Enigmatic Role of GBA2 in Controlling Locomotor Function.

The non-lysosomal glucosylceramidase GBA2 catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Loss of GBA2 function results in accumulation of glucosylceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP) and autosomal-recessive cerebellar ataxia (ARCA). Patients suffering from these disorders exhibit impaired locomotion and neurological abnormalities. GBA2 mutations found in these patients have been proposed to impair GBA2 function. However, the molecular mechanism underlying the occurrence of mutations in the GBA2 gene and the development of locomotor dysfunction is not well-understood. In this review, we aim to summarize recent findings regarding mutations in the GBA2 gene and their impact on GBA2 function in health and disease.