Interactions between calcium and alpha-synuclein in neurodegeneration

Abstract

In Parkinson's disease and some atypical Parkinson's syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson's disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity.

Figure 1

α-Synuclein protein (α-syn) domain structure. α-Syn contains three putative domains. KTK repeats in the N-terminus are involved in lipid interaction, the hydrophobic NAC domain is important for aggregation and the C-terminal Ca²⁺ binding site can increase the rate of oligomerization [1,2]. The Parkinson’s disease (PD)-linked point mutations are indicated within the neurotransmitter vesicle binding domain.

Figure 2

Raised intracellular Ca²⁺ promotes α-syn aggregation. (A) 1321N1 human glioma cells treated with either thapsigargin or Ca²⁺ ionophore caused raised intracellular free Ca²⁺ and induced α-syn aggregates (arrows) after 12–24 h [80]; (B) Potassium depolarization of SH-SY5Y human neuroblastoma and HEK293T cells resulted in transiently raised intracellular free Ca²⁺ and Lewy body-like large α-syn aggregates (arrows) that could be blocked by the BAPTA-AM Ca²⁺ chelator [81]. (C) Co-treatment of 1321N1 cells with thapsigargin (TG) or Ca²⁺ ionophore (CI) and hydrogen peroxide resulted in increased α-syn aggregates (arrows; graph, right); consistent with a cooperative interaction between raised free Ca²⁺ and oxidative stress [87]. Scale bars, 10 μm.

Figure 3

Unilateral rotenone lesion mouse (oxidative stress) model of PD shows α-syn aggregates primarily in calbindin-negative neurons. (A) CB+ neurons (arrowheads) showed relative protection in the unilateral rotenone lesion (oxidative stress) model of PD (as detailed in [85]), with more CB+ neurons surviving in the treated than in the untreated hemisphere and partitioning of α-syn aggregates (arrow) in the CB− neurons [86]. Scale bar, 50 μm. (B) Graph of cell counting data shows a significantly greater number of α-syn aggregates occur in CB− neurons than in CB+ neurons.