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: Benjamin Liou, Yanyan Peng, Ronghua Li, Venette Inskeep, Wujuan Zhang, Brian Quinn, Nupur Dasgupta, Rachel Blackwood, Kenneth D R Setchell, Sheila Fleming, Gregory A Grabowski, John Marshall, Ying Sun
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 25 Issue 23 Pg. 5126-5141 (12 01 2016) ISSN: 1460-2083 [Electronic] England
• PMID: 27655403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Neuroprotective Agents
• Ryanodine Receptor Calcium Release Channel
• Dantrolene

Topics

• Animals
• Calcium Signaling (genetics)
• Dantrolene (administration & dosage)
• Disease Models, Animal
• Gaucher Disease (drug therapy, genetics, physiopathology)
• Humans
• Mice
• Mitochondria (drug effects, genetics, pathology)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (administration & dosage)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)