Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation
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Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation. / Betzer, Cristine; Lassen, Louise Berkhoudt; Olsen, Anders; Kofoed, Rikke Hahn; Reimer, Lasse; Gregersen, Emil; Zheng, Jin; Calì, Tito; Gai, Wei Ping; Chen, Tong; Moeller, Arne; Brini, Marisa; Fu, Yuhong; Halliday, Glenda; Brudek, Tomasz; Aznar, Susana; Pakkenberg, Bente; Andersen, Jens Peter; Jensen, Poul Henning.
In: EMBO Reports, Vol. 19, No. 5, e44617, 2018.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation
AU - Betzer, Cristine
AU - Lassen, Louise Berkhoudt
AU - Olsen, Anders
AU - Kofoed, Rikke Hahn
AU - Reimer, Lasse
AU - Gregersen, Emil
AU - Zheng, Jin
AU - Calì, Tito
AU - Gai, Wei Ping
AU - Chen, Tong
AU - Moeller, Arne
AU - Brini, Marisa
AU - Fu, Yuhong
AU - Halliday, Glenda
AU - Brudek, Tomasz
AU - Aznar, Susana
AU - Pakkenberg, Bente
AU - Andersen, Jens Peter
AU - Jensen, Poul Henning
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - aggregation
KW - alpha-synuclein
KW - calcium
KW - endoplasmic reticulum
KW - SERCA
U2 - 10.15252/embr.201744617
DO - 10.15252/embr.201744617
M3 - Journal article
C2 - 29599149
AN - SCOPUS:85044500745
VL - 19
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 5
M1 - e44617
ER -
ID: 213961802