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.

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

“…While this model does not attempt to explain what causes an individual to develop IBM, it does connect many pathological elements observed in IBM biopsies. In the initiation [of Ca 2+ dysregulation] phase, one or more of the following may provide an initial insult to myofiber Ca 2+ homeostasis: i) sarcolemma damage and subsequent osmotic stress stemming from expanded and potentially-aggressive cytotoxic T-lymphocytes (CTLs) [16, 20, 44]; ii) alterations in Ca 2+ channel function and/or mitochondrial Ca 2+ buffering due to cytotoxic protein oligomers or fibrils [1, 11, 34, 46]; and/or iii) diminishment of SERCA function caused by calpain-3 reduction [39, 51]. Without amelioration of such insult(s) to Ca 2+ homeostasis, Ca 2+ dysregulation progresses in the propagation phase.…”

“…Although Ca 2+ regulation has not yet been investigated in human cases of IBM, data exist suggesting that some proteins associated with IBM can mediate an insult to Ca 2+ homeostasis [1, 11, 34, 46]. Additionally, abnormal Ca 2+ regulation may plausibly stem from membrane pores and osmotic stress, as clonal cytotoxic T-cells (expressing membranolytic enzymes) have been reported in IBM and may have a particularly aggressive phenotype [16, 20, 44].…”

Calcium and Parkinson's disease

“…These gradients are maintained by ATP-dependent pumps, whose sustained engagement creates a contuous bioenergetic burden for the cells [80,81]. Lastly, Ca 2+ promotes αSYN aggregation [82,83,84,85], because the Ca 2+ -dependent protease calpain cleaves off the carboxyl-terminus of αSYN, promoting aggregation [86]. This is further enhanced by oxidative stress [87] or DA [88].…”

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

“…The second downside is that this mechanism results in sustained elevations in cytosolic Ca 2+ concentration. Ca 2+ promotes aSYN aggregation both directly (Rcom-H'cheo-Gauthier et al, 2014) and indirectly through activation of calpain and calcineurin (Caraveo et al, 2014; Diepenbroek et al, 2014; Dufty et al, 2007). Elevated cytosolic Ca 2+ also impairs lysosomal function and turnover of misfolded proteins (Gómez-Sintes et al, 2016; Medina and Ballabio, 2015), potentially synergizing with other defects in proteasomal/autophagic function to increase the likelihood of LP (Wong and Cuervo, 2010).…”