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

Emmanouela Leandrou,Evangelia Emmanouilidou,Kostas Vekrellis

doi:10.3389/fnmol.2019.00237

Abstract

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.

Highlights

The affected neurons in Parkinson’s disease (PD) brains contain dense filamentous inclusions called Lewy bodies that primarily consist of the presynaptic protein α-synuclein (α-syn), a small neuronal protein that is abundant throughout the central nervous system under normal conditions (Goedert et al, 2017)
In this review we focus on the role of voltage-gated calcium channels (VGCCs) in PD and especially in neuronal degeneration that is apparent in PD
We can conclude that all different types of VGCCs have been implicated in the progressive neurodegeneration present in PD

Summary

Introduction

The affected neurons in Parkinson’s disease (PD) brains contain dense filamentous inclusions called Lewy bodies that primarily consist of the presynaptic protein α-synuclein (α-syn), a small neuronal protein that is abundant throughout the central nervous system under normal conditions (Goedert et al, 2017). It is possible that abnormal function of the specific Ca2+ channel(s) regulating α-syn secretion could alter the levels of α-syn released to the extracellular space in a manner that favors the local aggregation of the protein at least in certain extra-synaptic sites.

Results

Conclusion