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Alpha‐synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation |
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| Authors: | Cristine Betzer Louise Berkhoudt Lassen Anders Olsen Rikke Hahn Kofoed Lasse Reimer Emil Gregersen Jin Zheng Tito Calì Wei‐Ping Gai Tong Chen Arne Moeller Marisa Brini Yuhong Fu Glenda Halliday Tomasz Brudek Susana Aznar Bente Pakkenberg Jens Peter Andersen Poul Henning Jensen |
| Affiliation: | 1. Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark;2. Department of Biomedicine, Aarhus University, Aarhus, Denmark;3. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark;4. Department of Biomedical Sciences, University of Padova, Padova, Italy;5. Neuropathological Laboratory, Department of Medicine, Center for Neurological Diseases, University of Adelaide, Adelaide, SA, Australia;6. Department of Medical Biochemistry, School of Medicine, Flinders University, SA, Australia;7. Department of Structural Biology, Max Plank Institute of Biophysics, Frankfurt, Germany;8. Department of Biology, University of Padova, Padova, Italy;9. Brain & Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia;10. Research Laboratory for Stereology and Neuroscience, Bispebjerg‐Frederiksberg Hospital, Copenhagen, Denmark |
| 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. |
| Keywords: | aggregation alpha‐synuclein calcium endoplasmic reticulum SERCA |