α-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models

• Published in: Science (American Association for the Advancement of Science) 2006-07, Vol.313 (5785), p.324-328
• Main Authors: Cooper, Antony A, Gitler, Aaron D, Cashikar, Anil, Haynes, Cole M, Hill, Kathryn J, Bhullar, Bhupinder, Liu, Kangning, Xu, Kexiang, Strathearn, Katherine E, Liu, Fang, Cao, Songsong, Caldwell, Kim A, Caldwell, Guy A, Marsischky, Gerald, Kolodner, Richard D, LaBaer, Joshua, Rochet, Jean-Christophe, Bonini, Nancy M, Lindquist, Susan
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animal models; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Cell Survival; Cells, Cultured; Disease Models, Animal; Dopamine - physiology; Drosophila; Endoplasmic Reticulum - metabolism; Gene Expression; Gene Library; Genetic screening; Golgi Apparatus - metabolism; Humans; Mice; Midbrain; Nerve Degeneration; Neurodegenerative diseases; Neurons; Neurons - cytology; Neurons - physiology; Neuroscience; Open reading frames; Parkinson's disease; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Parkinsonian Disorders - physiopathology; Proteasome Endopeptidase Complex - metabolism; Protein Folding; Protein Transport; Proteins - chemistry; Proteins - metabolism; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; rab1 GTP-Binding Proteins - genetics; rab1 GTP-Binding Proteins - metabolism; Rats; Recombinant Fusion Proteins - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Secretory pathway; Toxicity; Vacuoles; Yeasts
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1129462

Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.