title: Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.
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.
authors.affiliation: Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Geddie
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Shusei
authors.initials: S
authors.lastname: Hamamichi
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Hill
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017124:Conserved Sequence; D004351:Drug Resistance / Q000235:genetics*; D004843:Epistasis, Genetic / Q000187:drug effects / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D008345:Manganese / Q000633:toxicity*; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014018:Tissue Distribution; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000633:toxicity
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D008345:Manganese; C539310:YPK9 protein, S cerevisiae; D006180:Proton-Translocating ATPases