Abstract
The more than 30-year-old Calcium hypothesis postulates that dysregulation in calcium dependent processes in the aging brain contributes to its increased vulnerability and this concept has been extended to Alzheimer’s disease and Parkinson’s disease. Central to the hypothesis is that increased levels of intracellular calcium develop and contributes to neuronal demise. We have studied the impact on cells encountering a gradual build-up of aggregated α-synuclein, which is a central process to Parkinson’s disease and other synucleinopathies. Surprisingly, we observed a yet unrecognized phase characterized by a reduced cytosolic calcium in cellular and neuronal models of Parkinson’s disease, caused by α-synuclein aggregates activating the endoplasmic calcium ATPase, SERCA. Counteracting the initial phase with low calcium rescues the subsequent degenerative phase with increased calcium and cell death – and demonstrates this early phase initiates decisive degenerative signals. In this review, we discuss our findings in relation to literature on calcium dysregulation in Parkinson’s disease and dementia.
Highlights
In Parkinson’s disease (PD), dopaminergic neurons in the substantia nigra pars compacta have been the focus of interest for decades due to their disease-associated loss that gives rise to the striatal dopamine deficiency and motoric symptoms
We have previously demonstrated that decisive prodegenerative signals, like changes in gene expression and secreted signaling molecules are generated at early time points in human α-synuclein expressing immortalized rat oligodendroglial cells (OLN-93) encountering a progressive build-up of soluble α-synuclein aggregates (Kragh et al, 2009, 2013, 2014)
Considering the fenestrated nature of the nuclear membrane this will likely result in a decreased nuclear Ca2+ that may blunt the protective Ca2+ transient elicited by synaptic NMDA receptors (NMDAR) signaling
Summary
In Parkinson’s disease (PD), dopaminergic neurons in the substantia nigra pars compacta have been the focus of interest for decades due to their disease-associated loss that gives rise to the striatal dopamine deficiency and motoric symptoms. The autonomous firing of these dopaminergic (DA) neurons along with their large terminal fields causes a continuous and large influx of Ca2+ that in order to maintain low normal Ca2+ levels has to be balanced by active transport processes at the risk of oxidative stress (Surmeier, 2007; Dryanovski et al, 2013; Surmeier et al, 2017). In contrast to previous hypotheses focusing on loss of cells, this observation corroborates the existence of prolonged phase with reduced Ca2+ in neurons that encounter progressive build-up of α-synuclein aggregates (Betzer et al, 2018). This phase may contribute to symptomatology by changing the neurons contribution to functional motor and non-motor circuitries. More subtle changes in leakiness or efficiency of specific pumps could have fundamental, but slowly progressing effects on the brains ability to compensate with aging and age-related neurodegenerative diseases as put forth in the Ca2+-hypothesis (Khachaturian, 1984, 1994; Berridge, 2010)
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