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 HD patients 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 novel therapeutic target. We now show that intracellular calcium (Ca2+) leak via post-translationally 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 in both HD patients and in a murine model of HD (Q175). HD mice (Q175) with endoplasmic reticulum (ER) 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 identify RyRs as a potential novel therapeutic target.