Alpha‐synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation

Abstract

Aggregation of α‐synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca2+ and α‐synuclein aggregation. Analyses of cell lines and primary culture models of α‐synuclein cytopathology reveal an early phase with reduced cytosolic Ca2+ levels followed by a later Ca2+ increase. Aggregated but not monomeric α‐synuclein binds to and activates SERCA in vitro, and proximity ligation assays confirm this interaction in cells. The SERCA inhibitor cyclopiazonic acid (CPA) normalises both the initial reduction and the later increase in cytosolic Ca2+. CPA protects the cells against α‐synuclein‐aggregate stress and improves viability in cell models and in Caenorhabditis elegans in vivo. Proximity ligation assays also reveal an increased interaction between α‐synuclein aggregates and SERCA in human brains affected by dementia with Lewy bodies. We conclude that α‐synuclein aggregates bind SERCA and stimulate its activity. Reducing SERCA activity is neuroprotective, indicating that SERCA and down‐stream processes may be therapeutic targets for treating α‐synucleinopathies.

Stabilization of α-synuclein oligomers using formaldehyde

“…Transmission electron microscopy (TEM) revealed a twisted ribbon-like structure of the purified α-syn oligomers, which corresponds well with previous observation of oligomeric α-syn (Fig. 1D) [22]. The α-syn oligomers clearly differ from the well-ordered structure and size of the preformed α-syn fibrils (Fig.…”

“…We successfully cross-linked α-syn oligomers using FA, thereby increasing stability towards SDS and urea denaturation. This oligomer preparation binds neuronal proteins in a conformational specific manner [21, 22], and also bind the two conformational specific antibodies FILA and MJF14. The FA mediated crosslinking did not disturb the overall twisted ribbon-like oligomeric structure, the size of the oligomers, their antigenicity toward FILA and MJF14 or the crosslinked oligomers applicability as calibrators in an α-syn oligomer specific ELISA assay [23].…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…Similar findings have been described in neuronal models of Parkinson's disease, where α-synuclein aggregates trigger an increase in cytosolic [Ca 2+ ] [47][48][49], which is preceded by a transient decrease due to activation of the SERCA pump by the aggregates [50]. This phase appears to be important for cell damage, as SERCA inhibitors were able to increase viability in cellular models and in C. elegans in vivo [48]. Studies in amyotrophic lateral sclerosis models also show an increased Ca 2+ entry through AMPA-type glutamate receptors, increased ER Ca 2+ release, and mitochondrial Ca 2+ overload [51].…”

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

“…h Percentage of MHC-II and CD68-expressing monocytes (4 WT/saline, 4 WT/RvD1; 3 Syn/saline, 3 Syn/RvD1; MHC-II: ANOVA: genotype × treatment, F 1,10 = 6.20, P = 0.032; genotype, F 1,10 = 18.69, P = 0.002; treatment, F 1,10 = 9.653, P = 0.011; WT/saline-Syn/saline **P = 0.004, WT/RvD1-Syn/saline **P = 0.002, Syn/saline-Syn/RvD1 *P = 0.025 with Bonferroni's; CD68: ANOVA for genotype × treatment, F 1,10 = 7.05, P = 0.024; genotype, F 1,10 = 4.51, P = 0.060; treatment, F 1,10 = 9.651, P = 0.011; WT/saline-Syn/saline *P = 0.042, WT/RvD1-Syn/saline *P = 0.025, Syn/saline-Syn/ RvD1 *P = 0.021 with Bonferroni's). Source data are provided as a Source Data file NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11928-w ARTICLE investigation of the interplay between α-syn, Ca 2+ buffering and mitochondrial function in these animals would be of great interest, particularly since α-syn can interfere with SERCA function, resulting in dysregulation of cytosolic Ca 2+ levels 54 .…”