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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 ?-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.

SUBMITTER: Liou B

PROVIDER: S-EPMC6078635 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.

Liou Benjamin B Peng Yanyan Y Li Ronghua R Inskeep Venette V Zhang Wujuan W Quinn Brian B Dasgupta Nupur N Blackwood Rachel R Setchell Kenneth D R KD Fleming Sheila S Grabowski Gregory A GA Marshall John J Sun Ying Y

Human molecular genetics 20161201 23

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 eithe ...[more]

PMID: 27655403

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Project description:Background Gaucher disease (GD), a rare lysosomal storage disorder, is associated with considerable patient and caregiver burden. We examined the applicability of existing caregiver questionnaires and assessed the level of burden in caregivers of patients with GD. Methods This cross-sectional, non-interventional study was conducted in Japan. Caregivers of patients with confirmed GD (any type) were recruited (patient association group and referral) for pre-testing (May 2021) or the main survey (October–December 2021). Caregivers completed the Caregiver Impact Questionnaire (CIQ; 30 items) and Zarit Caregiver Burden Interview (ZBI; 22 items) on paper. Total CIQ and ZBI scores and subscores were determined overall and by GD type. Inter-item correlations and test-retest reliability (2 rounds, 2 weeks apart) were calculated. The relationship between caregiving duration and caregiver burden was also analyzed. Results Nine caregivers (type 2 [GD2]: n = 6; type 3 [GD3]: n = 3) and 25 caregivers (type 1 [GD1]: n = 2; GD2: n = 17; GD3: n = 6) completed the pre-test and main survey, respectively. In the main survey, mean total CIQ score, all CIQ subscores (except emotional function), and total ZBI score were highest in caregivers of patients with GD2 compared with caregivers of patients with GD1/GD3. High test-retest reliability (Kappa >0.6) was observed for 15 CIQ items and 16 ZBI items. CIQ and ZBI scores appeared to be positively correlated with each other and negatively correlated with caregiving duration. Conclusions The CIQ and ZBI are applicable, reliable measures to assess burden in caregivers of patients with GD in Japan. Caregiver burden was highest in caregivers of patients with GD2 and decreased with caregiving duration. Highlights • Gaucher disease (GD) imposes substantial burden on patients and their caregivers.• CIQ and ZBI are applicable and reliable to assess caregiver burden for GD in Japan.• Burden was highest in caregivers of patients with type 2 GD than other GD types.• Caregiver burden decreased with caregiving duration in type 2 GD.

Project description:BackgroundThe variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.Case presentationWe report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.ConclusionsThis case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

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Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.

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Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.

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