Increased copper toxicity in Saccharomyces cerevisiae lacking VPS35, a component of the retromer and monogenic Parkinson disease gene in humans.
The Saccharomyces cerevisiae gene VPS35 encodes a component of the retromer complex which is involved in vesicle transport from endosomes to the trans-Golgi network. Yeast and human VPS35 orthologs are highly conserved and mutations in human VPS35 cause an autosomal dominant form of late-onset Parkinson disease (PD). We now show that deletion of VPS35 in yeast (vps35Δ) leads to a dose-dependent growth defect towards copper. This increased sensitivity could be rescued by transformation with yeast wild-type VPS35 but not by the expression of a construct harboring the yeast equivalent (i.e. D686N) of the most commonly identified VPS35-associated PD mutation, p.D620N. In addition, we show that expression of one copy of α-synuclein, which is known to directly interact with copper, leads to a pronounced aggravation of copper toxicity in vps35Δ cells, thereby linking the regulation of copper homeostasis by Vps35p in yeast to one of the key molecules in PD pathophysiology.
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Nadine
N
Sowada
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Barbara
B
Stiller
Institute of Human Genetics, University of Ulm, Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: c.kubisch@uke.de.
Christian
C
Kubisch
D003300:Copper / Q000633:toxicity*; D055786:Gene Knockout Techniques; D005800:Genes, Fungal; D005816:Genetic Complementation Test; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D000070579:Parkinson Disease Associated Proteins / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D000070579:Parkinson Disease Associated Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D029701:Saccharomyces cerevisiae Proteins; C076106:VPS35 protein, S cerevisiae; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D051844:alpha-Synuclein; D003300:Copper
Copper; Heavy metal homeostasis; Parkinson disease; Retromer; VPS35; α-synuclein