Alpha-synuclein Is Part of a Diverse and Highly Conserved Interaction Network That Includes PARK9 and Manganese Toxicity

Nat Genet. 2009 Mar;41(3):308-15. doi: 10.1038/ng.300. Epub 2009 Feb 1.

Abstract

Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Cells, Cultured
  • Conserved Sequence
  • Drug Resistance / genetics*
  • Epistasis, Genetic / drug effects
  • Epistasis, Genetic / physiology*
  • Gene Regulatory Networks / genetics
  • Gene Regulatory Networks / physiology
  • Manganese / toxicity*
  • Mutation / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics
  • Proton-Translocating ATPases / genetics*
  • Proton-Translocating ATPases / metabolism
  • Proton-Translocating ATPases / physiology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology
  • Tissue Distribution
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / physiology*
  • alpha-Synuclein / toxicity

Substances

  • Saccharomyces cerevisiae Proteins
  • alpha-Synuclein
  • Manganese
  • YPK9 protein, S cerevisiae
  • Proton-Translocating ATPases