Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease
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,...
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American Society for Clinical investigation
2020-10-01
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doaj-2571f7edb8e3450db13b03455d26d59d2021-08-03T00:12:01ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-10-01519Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s diseaseHaikel DridiXiaoping LiuQi YuanSteve ReikenMohamad YehyaLeah SittenfeldPanagiota ApostolouJulie BuronPierre SicardStefan MateckiJérome ThireauClement MenuetAlain LacampagneAndrew R. MarksHuntington’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.https://doi.org/10.1172/jci.insight.140614Cell biologyTherapeutics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Haikel Dridi Xiaoping Liu Qi Yuan Steve Reiken Mohamad Yehya Leah Sittenfeld Panagiota Apostolou Julie Buron Pierre Sicard Stefan Matecki Jérome Thireau Clement Menuet Alain Lacampagne Andrew R. Marks |
spellingShingle |
Haikel Dridi Xiaoping Liu Qi Yuan Steve Reiken Mohamad Yehya Leah Sittenfeld Panagiota Apostolou Julie Buron Pierre Sicard Stefan Matecki Jérome Thireau Clement Menuet Alain Lacampagne Andrew R. Marks Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease JCI Insight Cell biology Therapeutics |
author_facet |
Haikel Dridi Xiaoping Liu Qi Yuan Steve Reiken Mohamad Yehya Leah Sittenfeld Panagiota Apostolou Julie Buron Pierre Sicard Stefan Matecki Jérome Thireau Clement Menuet Alain Lacampagne Andrew R. Marks |
author_sort |
Haikel Dridi |
title |
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease |
title_short |
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease |
title_full |
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease |
title_fullStr |
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease |
title_full_unstemmed |
Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease |
title_sort |
role of defective calcium regulation in cardiorespiratory dysfunction in huntington’s disease |
publisher |
American Society for Clinical investigation |
series |
JCI Insight |
issn |
2379-3708 |
publishDate |
2020-10-01 |
description |
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. |
topic |
Cell biology Therapeutics |
url |
https://doi.org/10.1172/jci.insight.140614 |
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