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.

Spatial and Functional Crosstalk between the Mitochondrial Na+-Ca2+ Exchanger NCLX and the Sarcoplasmic Reticulum Ca2+ Pump SERCA in Cardiomyocytes

“…It is now generally accepted that the physical contacts between mitochondria and the SR/ER, called mitochondria-associated membranes (MAM), are crucial to Ca 2+ signaling, reactive oxygen species production, autophagy, lipid metabolism, and so on, in various types of cells. Above all, Ca 2+ transfer from the SR/ER to the mitochondria via the inositol-1,4,5 triphosphate receptor (IP 3 R) on the SR/ER, the voltage dependent anion channels (VDACs) on the outer membrane of mitochondria, and the CU mit on the inner membrane of mitochondria, have been well studied (see reviews [ 37 , 38 , 39 , 40 ]). In the heart, the impairment of the Ca 2+ transfer from the SR to the mitochondria via the IP 3 R–VDAC–CU mit axis, which was observed in the mouse model of diabetic cardiomyopathy, disrupted the mitochondrial bioenergetics while the excitation–contraction coupling was unaffected [ 41 ].…”

Protein kinase R dependent phosphorylation of α-synuclein regulates its membrane binding and aggregation

“…Dot blotting was performed as previously described ( 83 ) where 100 ng of protein was blotted on a nitrocellulose membrane (Hydrobond-C Extra, GE Healthcare). All membranes were blocked in nonfat milk (TBS with 5% nonfat milk, 0.05% Tween 20 and 0.02% sodium azide) for 30 min at RT followed by incubation with primary antibodies overnight.…”

Mitochondrial calcium cycling in neuronal function and neurodegeneration

“…The most common familial form of PD is caused by mutations in leucine-rich repeat kinase 2 (LRRK2) (Lee et al, 2019;Kovacs et al, 2021). Experiments in astrocytes identified that mutant…”

“…The reduced uptake of Ca 2+ into the ER increases ER stress and leads to mitochondrial Ca 2+ overload (Figure 3) (Lee et al, 2019;Kovacs et al, 2021;Modesti et al, 2021). Human fibroblasts from patients with LRRK2 mutations show upregulation of MCU and MICU1, and mitochondria have increased Ca 2+ uptake (Verma et al, 2017;Modesti et al, 2021).…”