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Parkinson's disease mechanism discovered

so they could determine which abnormalities arose earliest in the pathological process. Those experiments by Cooper revealed that an important early defect affected the machinery that transports proteins between two major cellular organelles -- the endoplasmic reticulum (ER) and the Golgi apparatus. The endoplasmic reticulum is the site of protein production, and the Golgi apparatus is the cell's "post office," which modifies, sorts and adds the molecular addresses that designate the specific destinations in the cell where proteins are needed.

Lindquist and her colleagues had conducted a genetic screen in yeast to discover genes whose activity affected the toxicity of alpha-synuclein. That study showed that genes enhancing ER-to-Golgi trafficking prevented alpha-synuclein toxicity. In particular, they found that one protein, called Ypt1p, which is involved in regulating trafficking could also be switched on to suppress alpha-synuclein toxicity in yeast cells.

"Our findings indicated that this ER-to-Golgi trafficking pathway is intimately coupled to the pathology, although in humans there are likely others involved as well, given how many genes we found that modified alpha-synuclein toxicity," said Lindquist. "But these findings were so persuasive that we decided we needed to test whether enhancing Ypt1p activity would suppress alpha-synuclein toxicity in animal models of the disease. Fortunately, we had an excellent team of collaborators with expertise in these models, who could conduct these studies."

The researchers next studied whether enhancing activity of the mammalian Ytp1p counterpart, called Rab1, suppressed alpha-synuclein toxicity in the fruitfly Drosophila, the roundworm C. elegans and in cultures of rat neurons. Bonini and her colleagues tested the effect in fruitflies; co-author Guy Caldwell and his colleagues at the University of Alabama performed the tests in roundworms; and co-author Jean-Christophe Roche and his colleagues at
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Source:Howard Hughes Medical Institute


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