RESUMEN
GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.
Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Inhibidores Enzimáticos/uso terapéutico , Gangliosidosis GM1/tratamiento farmacológico , Glicoesfingolípidos/metabolismo , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Heces/química , Gangliosidosis GM1/inmunología , Gangliosidosis GM1/metabolismo , Gangliosidosis GM1/fisiopatología , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Glicoesfingolípidos/antagonistas & inhibidores , Humanos , Activación de Macrófagos/efectos de los fármacos , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , beta-Galactosidasa/antagonistas & inhibidores , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.