Voltage-Gated Calcium Channels and α-Synuclein: Implications in Parkinson's Disease

Alpha-synuclein (alpha-syn) is biochemically and genetically linked to Parkinson's disease (PD) and other synucleinopathies. It is now widely accepted that alpha-syn can be released in the extracellular space, even though the mechanism of its release is still unclear. In addition, pathology-related aggregated species of alpha-syn have been shown to propagate between neurons in synaptically connected areas of the brain thereby assisting the spreading of pathology in healthy neighboring neuronal cells. In neurons, calcium channels are key signaling elements that modulate the release of bioactive molecules (hormones, proteins, and neurotransmitters) through calcium sensing. Such calcium sensing activity is determined by the distinct biophysical and pharmacological properties and the ability of calcium channels to interact with other modulatory proteins. Although the function of extracellular alpha-syn is currently unknown, previous work suggested the presence of a calcium-dependent mechanism for alpha-syn secretion both in vitro, in neuronal cells in culture, and also in vivo, in the context of a trans-neuronal network in brain. Mechanisms regulating extracellular alpha-syn levels may be of particular importance as they could represent novel therapeutic targets. We discuss here how calcium channel activity may contribute to alpha-syn aggregation and secretion as a pathway to disease progression in synucleinopathies.