The Ca2+/Mn2+ Ion-Pump PMR1 Links Elevation of Cytosolic Ca(2+) Levels to α-synuclein Toxicity in Parkinson's Disease Models

Cell Death Differ. 2013 Mar;20(3):465-77. doi: 10.1038/cdd.2012.142. Epub 2012 Nov 16.

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 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 αSyn-driven changes in Ca(2+) homeostasis and cytotoxicity. Expression of αSyn 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 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 Ca(2+) levels is pivotal for its cytotoxicity and requires PMR1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Calcium / metabolism*
  • Calcium-Transporting ATPases / deficiency
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism*
  • Humans
  • Manganese / metabolism
  • Models, Biological*
  • Molecular Chaperones
  • Oxidative Stress
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / toxicity

Substances

  • Caenorhabditis elegans Proteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • SSC1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • alpha-Synuclein
  • pmr-1 protein, C elegans
  • Manganese
  • Calcium-Transporting ATPases
  • Calcium
  • Acetylcysteine