Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis.
Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.
Soper
James H
JH
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. soper@mail.med.upenn.edu
Kehm
Victoria
V
Burd
Christopher G
CG
Bankaitis
Vytas A
VA
Lee
Virginia M-Y
VM
D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D020559:Monomeric GTP-Binding Proteins; C499307:YPT6 protein, S cerevisiae; D020691:rab GTP-Binding Proteins