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

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  • Cristine Betzer
  • Louise Berkhoudt Lassen
  • Anders Olsen, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • ,
  • Rikke Hahn Kofoed
  • Lasse Reimer
  • Emil Gregersen
  • Jin Zheng
  • Tito Calì, Department of Biomedical Sciences and CNR Institute of Neurosciences, University of Padova, Padua, Italy.
  • ,
  • Wei-Ping Gai, Neuropathological Laboratory, Department of Medicine, Center for Neurological Diseases, University of Adelaide, Adelaide, SA, Australia.
  • ,
  • Tong Chen, Department of Medical Biochemistry, School of Medicine, Flinders University, Bedford Park, SA, Australia.
  • ,
  • Arne Moeller
  • Marisa Brini, Department of Biology, University of Padova, Padova, Italy
  • ,
  • Yuhong Fu, Brain & Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
  • ,
  • Glenda Halliday, Brain & Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
  • ,
  • Tomasz Brudek, Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark.
  • ,
  • Susana Aznar, Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark.
  • ,
  • Bente Pakkenberg, Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark.
  • ,
  • Jens Peter Andersen
  • Poul Henning Jensen

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.

Original languageEnglish
JournalEMBO Reports
Volume19
Issue5
ISSN1469-221X
DOIs
Publication statusPublished - 1 May 2018

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