RIPK3 as a potential therapeutic target for Gaucher's disease

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.

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

“…38 Altogether, these findings suggest opportunities for RIPK3 inhibitors in the treatment of diseases where high RIPK3 kinase activity promotes human pathologies, also including steatohepatitis 36 and Gaucher's disease. 39 Materials and Methods Cell lines. Primary MEFs were generated by mating animals of the required genotypes and harvesting embryos at E12-E14 based on palpation.…”

The MLKL Channel in Necroptosis Is an Octamer Formed by Tetramers in a Dyadic Process

“…Studies in recent years have demonstrated the involvement of necroptosis in a number of pathophysiological processes, such as atherosclerosis (6), skin inflammation (7)(8)(9), chronic intestinal inflammation (10, 11), Gaucher's disease (12), acute liver injury (13,14), and heightened intestinal inflammation (15).…”

Necropotosis: a new link between cell death and inflammation

“…RIP3 knockout can significantly ameliorate the development of disease and prolong the survival of animals. [38] Amyotrophic lateral sclerosis (ALS) is the most adult onset motor neuron degenerative disease, in which inflammation is the most striking hallmark of pathological changes. Recently, it has been demonstrated that in the spinal cord of the ALS model, motor neurons also undergo necroptosis.…”