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

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

doi:10.15252/embr.201744617

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

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^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

31 Citationer (Scopus)

55 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	e44617
Tidsskrift	EMBO Reports
Vol/bind	19
Udgave nummer	5
Antal sider	21
ISSN	1469-221X
DOI	https://doi.org/10.15252/embr.201744617
Status	Udgivet - 2018

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10.15252/embr.201744617Licens: CC BY-NC-ND

Alpha‐synuclein aggregates activate calcium pump SERCA leading to calcium dysregulationForlagets udgivne version, 2,05 MBLicens: CC BY-NC-ND

Citationsformater

Betzer, C., Lassen, L. B., Olsen, A., Kofoed, R. H., Reimer, L., Gregersen, E., Zheng, J., Calì, T., Gai, W. P., Chen, T., Moeller, A., Brini, M., Fu, Y., Halliday, G., Brudek, T., Aznar, S., Pakkenberg, B., Andersen, J. P., & Jensen, P. H. (2018). Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation. EMBO Reports, 19(5), Artikel e44617. https://doi.org/10.15252/embr.201744617

Betzer, C, Lassen, LB, Olsen, A, Kofoed, RH, Reimer, L, Gregersen, E, Zheng, J, Calì, T, Gai, WP, Chen, T, Moeller, A, Brini, M, Fu, Y, Halliday, G, Brudek, T, Aznar, S, Pakkenberg, B, Andersen, JP & Jensen, PH 2018, 'Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation', EMBO Reports, bind 19, nr. 5, e44617. https://doi.org/10.15252/embr.201744617

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title = "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.",

keywords = "aggregation, alpha-synuclein, calcium, endoplasmic reticulum, SERCA",

author = "Cristine Betzer and Lassen, {Louise Berkhoudt} and Anders Olsen and Kofoed, {Rikke Hahn} and Lasse Reimer and Emil Gregersen and Jin Zheng and Tito Cal{\`i} and Gai, {Wei Ping} and Tong Chen and Arne Moeller and Marisa Brini and Yuhong Fu and Glenda Halliday and Tomasz Brudek and Susana Aznar and Bente Pakkenberg and Andersen, {Jens Peter} and Jensen, {Poul Henning}",

year = "2018",

doi = "10.15252/embr.201744617",

language = "English",

volume = "19",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Wiley-Blackwell",

number = "5",

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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

SN - 1469-221X

VL - 19

JO - EMBO Reports

JF - EMBO Reports

IS - 5

M1 - e44617

ER -

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

Abstract

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