RIPK3 as a potential therapeutic target for Gaucher's disease.
Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury.
1] Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel. [2].
Einat B
EB
Vitner
1] Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel. [2].
Ran
R
Salomon
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Tamar
T
Farfel-Becker
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Anna
A
Meshcheriakova
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Mohammad
M
Ali
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Andrés D
AD
Klein
Department of Pharmacology, University of Oxford, Oxford, UK.
Frances M
FM
Platt
Department of Medicine, University of Cambridge, Cambridge, UK.
Timothy M
TM
Cox
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Anthony H
AH
Futerman
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D005452:Fluoresceins; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*
D005452:Fluoresceins; C534582:fluoro-jade C; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse