A collaborative study of scientists from the Institute of Innate Immunity, research center caesar, and DZNE sheds light on the molecular mechanism underlying ataxia and spasticity in patients with mutations in a key enzyme of the glycosphingolipid metabolism.
GBA2 is a pivotal enzyme in lipid metabolism as it regulates the degradation of glucosylceramide. Glucosylceramide is a precursor lipid for other, more complex lipids, which are involved in maintaining key cellular functions. An imbalance in the glucosylceramide lipid homeostasis causes severe diseases that commonly affect the central nervous system. Mutations in the GBA2 gene have been identified in ataxic and spastic patients suffering from autosomal-recessive cerebellar ataxia (ARCA), hereditary spastic paraplegia (HSP), or the Marinesco-Sjögren-like syndrome. These patients exhibit impaired locomotion and neurological abnormalities that develop early in childhood and to date are incurable. The group of Dagmar Wachten could show that the mutations found in patients caused a loss of GBA2 function. Thus, to study the role of GBA2 in controlling locomotion, the researchers used a mouse model that lacks GBA2 (GBA2 knockout-mice) and analyzed the gait properties compared to control mice. Indeed, GBA2 knockout-mice displayed alterations in their gait pattern and some of them displayed a strong defect in locomotion. However, the phenotype did not fully resemble the human phenotype, suggesting species-specific differences in GBA2-controlled glucosylceramide metabolism. To study the defect on a cellular level, the morphology and function of neurons was analyzed in a petri dish. Loss of GBA2 activity had a strong defect on neuronal development and morphology, in particular on the outgrowth of cellular extensions, called neurites, which are important to transmit information in the brain from one neuron to the other. This demonstrated that the lipid homeostasis is crucial for neuronal development and sheds light on how mutations in the GBA2 gene might cause locomotor dysfunction.
Original publication: M.A. Woeste, S. Stern, D.N. Raju, E. Grahn, D. Dittmann, K. Gutbrod, P. Dörmann, J.N. Hansen., S. Schonauer, C.E. Marx, H. Hamzeh, H.G. Körschen, J.M.F.G. Aerts, W. Bönigk, H. Endepols, R. Sandhoff, M. Geyer, T.K. Berger., F. Bradke, und D. Wachten - Species-specific differences in non-lysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. Journal of Biological Chemistry, doi:10.1074/ jbc.RA118.006311