TY - JOUR
T1 - The Ca 2+ /Mn 2+ ion-pump PMR1 links elevation of cytosolic Ca 2+ levels to -synuclein toxicity in Parkinson's disease models
AU - Büttner, S.
AU - Faes, L.
AU - Reichelt, W. N.
AU - Broeskamp, F.
AU - Habernig, L.
AU - Benke, S.
AU - Kourtis, N.
AU - Ruli, D.
AU - Carmona-Gutierrez, D.
AU - Eisenberg, T.
AU - D'Hooge, P.
AU - Ghillebert, R.
AU - Franssens, V.
AU - Harger, A.
AU - Pieber, T. R.
AU - Freudenberger, P.
AU - Kroemer, G.
AU - Sigrist, S. J.
AU - Winderickx, J.
AU - Callewaert, G.
AU - Tavernarakis, N.
AU - Madeo, F.
N1 - Funding Information:
Acknowledgements. This work was supported by the Austrian Science Fund FWF (Grants T414-B09 and V235-B09 to SB, Grant S-9304-B05 to FM and DC-G, P23490-B12 to FM and WNR, P24381-B20 to FM and TE, LIPOTOX to FM and DR and DK-MCD to FM and LH), the European Research Council (ERC to NT), the European Commission (Apo-Sys to FM and TE), the Scientific Research Flanders (Grant G.0498.09 to GC), the University of Leuven (to JW and Grant OT/07/069 to GC), the Herculus funding (Grant HER/08/066 to GC) and the FWO-Vlaanderen and IWT-Vlaanderen (SBO-NeuroTarget to JW).
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein -synuclein (Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca 2+ fluxes, arguing for an involvement of deregulated Ca 2+ homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca 2+ /Mn 2+ ATPase PMR1 (plasma membrane-related Ca 2+ -ATPase 1) as a phylogenetically conserved mediator of Syn-driven changes in Ca 2+ homeostasis and cytotoxicity. Expression of Syn in yeast resulted in elevated cytosolic Ca 2+ levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the Syn-driven rise of cytosolic Ca 2+ levels is pivotal for its cytotoxicity and requires PMR1.
AB - Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein -synuclein (Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca 2+ fluxes, arguing for an involvement of deregulated Ca 2+ homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca 2+ /Mn 2+ ATPase PMR1 (plasma membrane-related Ca 2+ -ATPase 1) as a phylogenetically conserved mediator of Syn-driven changes in Ca 2+ homeostasis and cytotoxicity. Expression of Syn in yeast resulted in elevated cytosolic Ca 2+ levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the Syn-driven rise of cytosolic Ca 2+ levels is pivotal for its cytotoxicity and requires PMR1.
KW - Ca homeostasis
KW - PMR1
KW - Parkinson's disease models
KW - a-synuclein
KW - dopaminergic neuron loss
KW - yeast cell death
UR - http://www.scopus.com/inward/record.url?scp=84873703372&partnerID=8YFLogxK
U2 - 10.1038/cdd.2012.142
DO - 10.1038/cdd.2012.142
M3 - Article
C2 - 23154387
AN - SCOPUS:84873703372
SN - 1350-9047
VL - 20
SP - 465
EP - 477
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 3
ER -