Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington's disease.

Haikel Dridi,Pierre Sicard,Andrew R Marks,Stefan Matecki,Qi Yuan,Xiaoping Liu,Julie Buron,Mohamad Yehia,Panagiota Apostolou,Jérome Thireau,Alain Lacampagne,Clement Menuet,Steve Reiken,Leah Sittenfeld

doi:10.1172/jci.insight.140614

Haikel Dridi, Pierre Sicard + Show 12 more

Open Access

https://doi.org/10.1172/jci.insight.140614

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Abstract

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder affecting striatal neurons beginning in young adults with loss of muscle coordination and cognitive decline. Less appreciated is the fact that patients with HD also exhibit cardiac and respiratory dysfunction, including pulmonary insufficiency and cardiac arrhythmias. The underlying mechanism for these symptoms is poorly understood. In the present study we provide insight into the cause of cardiorespiratory dysfunction in HD and identify a potentially novel therapeutic target. We now show that intracellular calcium (Ca2+) leak via posttranslationally modified ryanodine receptor/intracellular calcium release (RyR) channels plays an important role in HD pathology. RyR channels were oxidized, PKA phosphorylated, and leaky in brain, heart, and diaphragm both in patients with HD and in a murine model of HD (Q175). HD mice (Q175) with endoplasmic reticulum Ca2+ leak exhibited cognitive dysfunction, decreased parasympathetic tone associated with cardiac arrhythmias, and reduced diaphragmatic contractile function resulting in impaired respiratory function. Defects in cognitive, motor, and respiratory functions were ameliorated by treatment with a novel Rycal small-molecule drug (S107) that fixes leaky RyR. Thus, leaky RyRs likely play a role in neuronal, cardiac, and diaphragmatic pathophysiology in HD, and RyRs are a potential novel therapeutic target.

Highlights

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder affecting striatal neurons in young adults with distinct symptoms of cognitive decline and muscle incoordination [1, 2]
Neuronal RyR2 channels are leaky in patients with HD and in a murine model of HD
In pathological conditions, remodeled ryanodine receptor (RyR) channels have been shown to mediate ER/SR Ca2+ leak into the cytosol at rest, leading to local increases of [Ca2+]cyt and activation of pathological signals [60]

Summary

Introduction

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder affecting striatal neurons in young adults with distinct symptoms of cognitive decline and muscle incoordination [1, 2]. This devastating disease is usually fatal approximately 10–15 years after onset of symptoms, and there is no disease-modifying treatment. Patients with HD exhibit impaired locomotor and respiratory muscle function and digestive tract dysfunction [4]. Most patients with HD do not report respiratory symptoms until later stages of the disease, when impaired swallowing and respiratory muscle weakness cause fatal aspiration pneumonias [7, 11, 14]. Patients with HD exhibited reduced respiratory pressure, forced vital capacity, peak expiratory flow, and maximal voluntary ventilation [13]

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