title: Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.
abstract: Neuronopathic Gaucher disease (nGD) manifests as severe neurological symptoms in patients with no effective treatment available. Ryanodine receptors (Ryrs) are a family of calcium release channels on intracellular stores. The goal of this study is to determine if Ryrs are potential targets for nGD treatment. A nGD cell model (CBE-N2a) was created by inhibiting acid β-glucosidase (GCase) in N2a cells with conduritol B epoxide (CBE). Enhanced cytosolic calcium in CBE-N2a cells was blocked by either ryanodine or dantrolene, antagonists of Ryrs and by Genz-161, a glucosylceramide synthase inhibitor, suggesting substrate-mediated ER-calcium efflux occurs through ryanodine receptors. In the brain of a nGD (4L;C*) mouse model, expression of Ryrs was normal at 13 days of age, but significantly decreased below the wild type level in end-stage 4L;C* brains at 40 days. Treatment with dantrolene in 4L;C* mice starting at postnatal day 5 delayed neurological pathology and prolonged survival. Compared to untreated 4L;C* mice, dantrolene treatment significantly improved gait, reduced LC3-II levels, improved mitochondrial ATP production and reduced inflammation in the brain. Dantrolene treatment partially normalized Ryr expression and its potential regulators, CAMK IV and calmodulin. Furthermore, dantrolene treatment increased residual mutant GCase activity in 4L;C* brains. These data demonstrate that modulating Ryrs has neuroprotective effects in nGD through mechanisms that protect the mitochondria, autophagy, Ryr expression and enhance GCase activity. This study suggests that calcium signalling stabilization, e.g. with dantrolene, could be a potential disease modifying therapy for nGD.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Venette
authors.initials: V
authors.lastname: Inskeep
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Quinn
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Nupur
authors.initials: N
authors.lastname: Dasgupta
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Blackwood
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Fleming
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D003620:Dantrolene / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene