Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease

Abstract

Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, β 1 adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed, and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

“…In pre-clinical settings, the R6/2 mouse model -that displays impairment in cardiac functions -had significant alterations in mitochondrial structure, including the loss of mitochondrial elongated shapes and diffused mitochondrial densities [36,37]. These morphological changes may lead directly to cardiac energy metabolism imbalances.…”

Longitudinal Evaluation of theHdh(CAG)150Knock-In Murine Model of Huntington's Disease

“…The aggressive phenotype makes R6/2 very useful for preclinical pharmacology, but it is not an exact genetic or neuropathological analog of HD. R6/2 mice have widespread NII expression, a high incidence of epilepsy, diabetes, cardiac dysfunction, and neuromuscular junction abnormalities (Hurlbert et al, 1999;Meade et al, 2002;Ribchester et al, 2004;Mihm et al, 2007). The R6/2 line is a plausible model of juvenile-onset HD, in which the effects of the expanded polyglutamine repeat occurs in the context of a developing brain.…”

Proteostasis in cardiac health and disease

“…The best example of this hypothesis is Huntington disease, an autosomal dominant condition resulting from the expansion of the tri nucleotide CAG repeat ('polyQ repeat') in the hunting tin (HTT) gene. HF is among the leading causes of death in Huntington disease 114 , and the prevalence of HF in patients with Huntington disease is markedly increased com pared with age matched controls 115 [118][119][120] have demonstrated that whole body expression of polyQ proteins precipitates cardiomyopathy. Although this observation supports a direct involvement of the mutant huntingtin in development of cardiac disease, Huntington disease also features marked imbalance in the autonomic nervous system, leading to enhanced sympathetic tonus 121 , which might (partly) contribute to HF in Huntington disease.…”