Glycosphingolipids in murine neurodegenerative diseases

本研究的目的是开发一种有效的神经节苷脂储存病的终身治疗方法。

The objective of this research is to develop an effective life long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable neurodegenerative diseases involving storage of either ganglioside GM1 or GM2 in lysosomes. GM1 gangliosidosis arises from a genetic deficiency of the acid b- galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the b-hexosaminidase b subunit that catabolizes ganglioside GM2. Ganglioside accumulation in these diseases leads to neuronal death, inflammation, and progressive neurological deterioration. Our studies will involve diverse and complimentary approaches for disease management. This research will evaluate NB-DGJ as a substrate reduction therapy, neural stem cells (NSCs), as across-correctional therapy, and caloric restriction (CR) as an anti-inflammatory therapy. NB-DGJ decreases the rate of glyco- sphingolipid (GSL) biosynthesis thereby counterbalancing an impaired rate of catabolism. NSCs provide the missing lysosomal enzyme thereby reducing GSL storage, whereas CR improves health through effects on CNS inflammatory processes. Aim 1will determine the effects of NB-DGJ on the GSL composition of postnatal brains in normal mice and in the GM1 gangliosidosis and SD mutants. This aim will determine, a) the timing and extent of brain ganglioside recovery following NB-DGJ treatment, b) the extent to which GSL synthesis inhibition delays pathological ganglioside storage in CNS tissues, and c) whether GSL synthesis inhibition delays myelin abnormalities in the storage disease mice. Aim 2 will evaluate the therapeutic potential of neural stem cell (NSC) transplantation alone and together with NB-DGJ in developing SD mice. We hypothesize that NSCs will act synergistically with and NB-DGJ to reduce accumulating GSLs and provide maximal therapeutic effect. Aim 3 will examine the influence of NB-DGJ on embryo gangliosides following in utero administration. These studies will test the feasibility of timed drug release for in utero substrate reduction therapy for GM1 gangliosidosis. Aim 4 will test the hypothesis that CR reduces CNS inflammation and that CR and NB-DGJ act synergistically in managing CNS inflammation, ganglioside accumulation, and disease progression. The proposed studies will provide essential information on combinatorial therapies for the ganglioside storage diseases and will have translational benefit to the clinic.