Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies

Abstract

Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that α-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an α-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an α-synuclein transgenic C. elegans model. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP₃-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain α-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more α-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of α-synuclein to SERCA, RyR, IP₃R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.

Keywords: IP3R; Parkinson's disease; RyR; SERCA; calcium; endoplasmic reticulum; α-synuclein.

Figure 1

Disease modifying strategies for synucleinopathies by modulating aberrant Ca²⁺ fluxes in ER and mitochondria via targeting the SERCA pump, the RyR, and the ER-mitochondrial transport complex. α-syn is under normal conditions predominantly located in nerve terminals. In synucleinopathies, its initial aggregation is hypothesized to initiate at this site. From here, aggregates are transported retrograde through the axon to the cell body where Lewy bodies can form. (A) In healthy neurons the low resting Ca²⁺ level in the cytosol and the high Ca²⁺ levels in the ER and mitochondria are tuned by (1) the SERCA pump loading the ER with Ca²⁺ from the cytosol (red arrows), (2) the release of Ca²⁺ from ER to the cytosol by RyR and IP₃R (blue arrows), (3) where the latter is part of the multi-molecular Ca²⁺ funnel between ER lumen and the mitochondrial matrix (IP₃R, GRP75, VDAC1, mRyR, MCU, and RaM). (B) In synucleinopathies, the α-syn aggregates activate SERCA causing an increased Ca²⁺ uptake into the ER thereby deregulating ER functions and increasing the Ca²⁺ flux through the IP₃R-GRP75-VDAC1 complex and MCU into mitochondria. These increased Ca²⁺ fluxes into ER and mitochondria along with a decreased cytosolic Ca²⁺ concentration result in a reduced functionality and viability of neurons in synucleinopathies. The same pathways can be activated by mutant LRRK2-G2019S that activates SERCA and by loss-of-function genetic risk variants in the ITPKB kinase that increases the IP₃-dependent Ca²⁺ flux from ER to mitochondria. (C) These abnormal Ca²⁺ fluxes can be counteracted as a disease modifying strategy in synucleinopathies. The α-syn activated SERCA can be inhibited e.g., by CPA. The Ca²⁺ flux from ER to mitochondria can for example be attenuated by stimulating ITPKB or inhibiting the IP₄ phosphatase. The Ca²⁺ flux from ER into the cytosol can be stimulated by caffeine (white arrow) or other RyR activators.