Calcium: alpha-synuclein interactions in alpha-synucleinopathies

• Main Authors: Alexandre N. Rcom-H’cheo-Gauthier1, Samantha L. Osborne, Adrian C.B. Meedneniya, Dean Louis Pountney
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2016-12-01
• Series: Frontiers in Neuroscience
• Subjects: Parkinson’s disease1; α-synuclein2; Calcium3; Multiple system atrophy4; Dementia with Lewy Bodies5.
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00570/full

Aggregation of the pre-synaptic protein, α-synuclein (α-syn), is the key aetiological factor in Parkinson’s disease (PD) and other alpha-synucleinopathies, such as multiple system atrophy and Dementia with Lewy bodies. Various triggers for pathological α-syn aggregation have been elucidated, including port-translational modifications, oxidative stress and binding of metal ions, such as calcium. Raised neuronal calcium levels in PD may occur due to mitochondrial dysfunction and/or may relate to calcium channel dysregulation or the reduced expression of the neuronal calcium buffering protein, calbindin-D28k. Recent results on human tissue and a mouse oxidative stress model show that neuronal calbindin-D28k expression excludes α-syn inclusion bodies. Previously, cell culture model studies have shown that transient increases of intracellular free Ca(II), such as by opening of the voltage-gated plasma calcium channels, could induce cytoplasmic aggregates of α-syn. Raised intracellular free calcium and oxidative stress also act cooperatively to promote α-syn aggregation. The association between raised neuronal calcium, α-syn aggregation, oxidative stress and neurotoxicity is reviewed in the context of neurodegenerative α-syn disease and potential mechanism-based therapies.