Why the study?
Parkinson disease is associated with cardiac electrophysiological changes and sudden arrhythmic death linked to cardiac alpha-synucleinopathy, but the electrophysiological phenotype in alpha-synuclein models requires exploration.
In a mouse model of Parkinson's disease, the alpha-synuclein A30P mutation induces significant electrophysiological alterations in cardiac and stellate ganglia ionic channel gating properties, providing a potential mechanism for cardiac remodeling and arrhythmias in PD.
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Alters cardiac Na+ channel gating in A30P models; leaves open arrhythmia relevance in PD and needs clinical confirmation.
Background Parkinson’s disease (PD) has been associated with cardiac electrophysiological modifications in the patients, as indicated by their electrocardiogram (ECG), and the degree of changes in ECG correlated with the disease progression and severity. Recent studies have identified cardiac alpha-synucleinopathy in patients with PD, and the prevalence of sudden arrhythmic death among PD patients is correlated with the presence of cardiac alpha-synucleinopathy. In addition, alpha-synuclein aggregates have been shown to disrupt ionic currents in ventricular tissue. Purpose The present study explored the electrophysiological phenotype of alpha-synuclein (aSYN) human A30P mutant mice, as a PD animal model which develops cardiac alpha-synuclein pathology. Methods A loose patch clamp was utilized to investigate tissue-level electrophysiology. Using the PD animal model, we examined aSYN-mediated effect on voltage-gated ionic currents in the ventricle and stellate ganglia by quantifying the activation, inactivation, and time-dependent recovery from inactivation properties of sodium channels, as well as the activation and rectification properties of potassium currents, which are expected to reflect cardiac electrophysiological remodeling. Ionic currents from ventricular myocardium and stellate ganglia tissue from 5-month-old PD mice (n = 30 recordings, 7 mice per group) were compared to wild-type. Results We observed alteration of ionic channel gating properties for inward sodium currents in activation (p = 0.001 WT vs A30P), inactivation (p = 0.04), and time-dependent recovery from inactivation (p = 0.003) in the aSYN A30P mice. It reduced the maximum amplitude of currents during potassium current activation (p = 0.028) and rectification (p = 0.04). Additionally, the sodium activation and inactivation currents were altered in the stellate ganglia in the aSYN A30P mice. Conclusion We here demonstrate that cardiac electrophysiological alterations developing in the heart and stellate ganglia in a mouse model of PD. Understanding the pathophysiological changes induced by alpha-synucleinopathy will aid in identifying how aSYN alters electrophysiology, ultimately contributing to understanding the potential cardiac remodeling occurring in PD. Figure legend: Localisation of A30P mutant α-synuclein in the stellate ganglia and heart, and characterisation of inward sodium currents under loose patch-clamp recordings. A, Co-localisation of neuronal markers (TH, PGP9.5) with A30P mutant α-synuclein in the stellate ganglia (top) and ventricular myocardium (bottom) of the PD mouse model (WT vs A30P). A30P mutant protein co-localised with neuronal tissue markers in both tissues. Scale bar: 20 µm. B, Ex vivo loose patch-clamp recordings of inward sodium currents from stellate ganglia (top) and ventricular myocardium (bottom). (a) I–V curve and Boltzmann slope factor in stellate ganglia. (b) I–V curve and Boltzmann slope factor in ventricle.
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Lee et al. (2026) studied this question.
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