The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson’s disease models

Abstract

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 α-synuclein (αSyn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca2+ fluxes, arguing for an involvement of deregulated Ca2+ homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca2+/Mn2+ ATPase PMR1 (plasma membrane-related Ca2+-ATPase 1) as a phylogenetically conserved mediator of αSyn-driven changes in Ca2+ homeostasis and cytotoxicity. Expression of αSyn in yeast resulted in elevated cytosolic Ca2+ levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented αSyn-induced loss of dopaminergic neurons in nematodes and flies. In addition, αSyn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the αSyn-driven rise of cytosolic Ca2+ levels is pivotal for its cytotoxicity and requires PMR1.

Spermidine protects against α-synuclein neurotoxicity

“…36 For that purpose, we analyzed nematodes expressing human aSyn under the control of a dopamine-specific neuronal promoter (P dat-1 ) for survival of the anterior CEP (cephalic) dopaminergic neurons, which were visualized via co-expression of GFP driven by the dat-1 gene promoter. Consistent with previous findings, 31,32,36,37 the expression of aSyn caused severe dopaminergic neuron loss in 7-day-old adult worms compared to same-staged animals expressing GFP alone ( Fig. 2A), leading to less than 10% of worms with healthy, wild-type like CEPs (Fig.…”

“…This result prompted us to combine this genetic trigger of PD (aSyn) with the administration of manganese, which represents a known environmental risk factor for PD. 35 Employing this experimental setup, 31,32 pan-neuronal elav-GAL4-driven expression of aSyn killed the flies within 4-6 days (Fig. 1A).…”

“…[29][30][31][32] The protein aSyn is thought to play a pivotal role in the degenerative processes during PD, as it (i) represents the main protein component of the intracellular protein aggregates called Lewy bodies, a pathological hallmark of PD, and (ii) point mutations in as well as duplication/ triplication of the gene locus coding for aSyn are linked to familial PD. 33 Here, we demonstrate that supplementation of food with spermidine protects against aSyn-facilitated motor dysfunction and organismal death in flies and reduces dopaminergic neuron loss in nematodes while causing an activation of autophagy.…”

Calcineurin determines toxic versus beneficial responses to α-synuclein

“…For example, a profound disruption of Ca 2+ homeostasis is seen in Parkinson disease (PD), the second most common neurodegenerative disorder. Mutations or aberrant expression of α-synuclein (α-syn), a major protein involved in the pathogenesis of PD, can induce Ca 2+ overload and cell death (2)(3)(4)(5). Additional clinical and experimental observations highlight the importance of Ca 2+ homeostasis in the pathogenesis of PD.…”

“…Despite the compelling link between Ca 2+ homeostasis and PD, we know little about the signaling pathways driven by sustained Ca 2+ elevations and how they might lead to cell death (4,5). Yeast provide a powerful model system for such investigations, given their genetic tractability and the remarkable conservation of Ca 2+ -signaling pathways from yeast to humans (14,15).…”