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


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

Emmanouela Leandrou et al. Front Mol Neurosci.


Alpha-synuclein (α-syn) is biochemically and genetically linked to Parkinson's disease (PD) and other synucleinopathies. It is now widely accepted that α-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 α-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 α-syn is currently unknown, previous work suggested the presence of a calcium-dependent mechanism for α-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 α-syn levels may be of particular importance as they could represent novel therapeutic targets. We discuss here how calcium channel activity may contribute to α-syn aggregation and secretion as a pathway to disease progression in synucleinopathies.

Keywords: Parkinson’s and related diseases; alpha-synuclein; calcium; neurodegeneration; protein aggregation; secretion; voltage gated Ca2+ channel.


Interplay of α-syn and Ca2+. Elevation of intracellular Ca2+ levels through voltage-gated calcium channels (VGCCs) may lead to aggregation of α-syn via indirect interactions with calcium binding proteins such as Calmodulin, or via direct binding of Ca2+ to α-syn that leads to exposure of NAC domain (A), elevation of intracellular amounts of α-syn may lead to VGCCs opening and calcium influx that results in increased formation of reactive oxygen species (ROS) and neurodegeneration (B). It still remains unclear whether elevation of intracellular Ca2+ is the cause or the result of α-syn aggregation which promotes the release and propagation of α-syn -the release is accomplished either through exosomes or through other proposed secretory mechanisms (C).

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