Aggregation of alpha-Synuclein in S. cerevisiae is Associated with Defects in Endosomal Trafficking and Phospholipid Biosynthesis

作者：Soper James H^*; Kehm Victoria; Burd Christopher G; Bankaitis Vytas A; Lee Virginia M Y

来源：Journal of Molecular Neuroscience, 2011, 43(3): 391-405.

DOI：10.1007/s12031-010-9455-5

• Parkinson's disease
• Alpha-synuclein
• Neurodegenerative disease
• Vesicle trafficking
• Rab GTPase
• Yeast

Parkinson's disease is the most common neurodegenerative movement disorder. alpha-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 alpha-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of alpha-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of alpha-synuclein toxicity, but the exact role alpha-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that alpha-synuclein induces aggregation of many yeast Rab GTPase proteins, that alpha-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that alpha-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that alpha-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to alpha-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for alpha-synuclein neurotoxicity.

• 出版日期2011-3