Partial Molecular and Biochemical Characterization of a Sandhoff Mouse Model

Abstract

Sandhoff Disease (SD) is a rare genetic disorder which results in progressive neurodegeneration. SD is caused by a build-up of GM2 Gangliosides, a lipid which is stored in the lysosome of neurons. It can occur in infantile, juvenile and adult forms; in the severe, infantile form, death occurs by the age of 4. It is well understood that this lipid build-up is the result of a mutation of the HEXB gene, which results in a deficiency of the ‘beta-hexosaminidase A’ enzyme for which it codes; however, a better understanding of the pathology is needed. The objective of this study was, therefore, to better characterize SD to improve our understanding of the disease. This study took two approaches; the first approach was to monitor gene expression changes of six genes previously identified as showing increased expression the brains of 4 week old SD mice. Three of these genes were related to inflammation: Ccl3, Lyz, and Wfdc17; whilst three genes were related to myelination: Ugt8a, Fa2h, and Mog. They were assessed at 3 time points: 5 weeks, 10 weeks, and 16 weeks. Secondly, this study profiled metabolite changes in the serum and urine of SD mice, at the same time points, through the use of mass spectrometry. Gene expression analysis showed that there is an inflammatory response occurring from 5 weeks in SD mice that continues to increase over the course of the disease. Demyelination was also shown to occur, varying with disease progression. Metabolomic analysis showed a decrease in two metabolites of glycerophospholipids and acylcarnitines suggesting that the breakdown and synthesis is interrupted downstream of the GM2 Ganglioside storage. Lastly, consistent with other findings, we have shown amino acids (particularly alanine) to be elevated, which is a likely consequence of increased demand for energy following the interruption of lipid breakdown and reduced food intake. Whilst this study did not identify any candidate biomarkers for SD, it has contributed towards the understanding of the pathology behind the disease. Future studies will be needed to further characterize SD in mouse models and in humans.