Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease1. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease2. 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 expense3 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)4 and in nGD mouse models5,6,7. 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.
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We thank B. Cachón-González (University of Cambridge) for providing twitcher mouse tissue, D. Wallach (Weizmann Institute of Science, Israel) for providing Tnf and Ripk3 knockout mice, R. Schiffmann (Baylor Research Institute) for postmortem human brain tissue, V. Kiss (Weizmann Institute of Science) for help with fluorescence microscopy and N. Platt (University of Oxford) for helpful comments. This work was supported by the Children′s Gaucher Research Fund. A.H.F. is the incumbent of an endowed professorial chair supported by the Joseph Meyerhoff family. F.M.P. is a Royal Society Wolfson Research Merit Award holder.
The authors declare no competing financial interests.
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Vitner, E., Salomon, R., Farfel-Becker, T. et al. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat Med 20, 204–208 (2014). https://doi.org/10.1038/nm.3449
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