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- Title
RIPK3 as a potential therapeutic target for Gaucher's disease.
- Authors
Vitner, Einat B; Salomon, Ran; Farfel-Becker, Tamar; Meshcheriakova, Anna; Ali, Mohammad; Klein, Andrés D; Platt, Frances M; Cox, Timothy M; Futerman, Anthony H
- Abstract
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.
- Subjects
GAUCHER'S disease treatment; METABOLIC disorder treatment; NEUROLOGIC manifestations of general diseases; LYSOSOMAL storage diseases; GENETIC mutation; PARKINSON'S disease; DISEASE risk factors; RECEPTOR-interacting proteins
- Publication
Nature Medicine, 2014, Vol 20, Issue 2, p204
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3449