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“It's sort of like traffic on city streets, which is normally controlled by stoplights,” says Lindquist. “Here, it's like someone crashed at the intersection and nothing is getting through.” The extra ER-Golgi trafficking gene acts like a police officer directing cars past the wreck. “Our idea is that [the extra alpha-synuclein] is doing something generally toxic to all cells,” she says. “It's just that the dopamine-producing neurons are more sensitive and die earlier.”
One hazard for these cells is the dopamine. As soon as the unstable neurotransmitter is made, vesicles must quickly package it and shuttle it out of the neuron. If dopamine accumulates inside the neuron, it can degrade into destructive by-products, such as the reactive oxygen species found in Parkinson's patients.
Collaborator (and first author of the Science paper) Antony Cooper at the University of Missouri-Kansas City determined that the first signs of blocked ER-Golgi traffic happen early on in yeast with an overabundance of alpha-synuclein. He also noted that the genetic boosts were rescuing yeast by, in essence, turbocharging ER-Golgi traffic to override obstruction caused by the protein.
“At that point it became really interesting,” Lindquist says, “but it was just yeast.”
So Lindquist called fruit fly neurogeneticist Nancy M. Bonini, an HHMI investigator at the University of Pennsylvania, to see if the findings would hold up in animals with neurons and brains. Bonini had developed a Parkinson's model by overexpressing alpha-synuclein in dopamine-producing fly neurons. She found that the gene that made the most difference in the yeast also appeared to suppress toxicity in the fly model.
“Although a yeast cell is not a neuron,” Bonini says, “and nothing takes the place of [studies in] humans, this is an example of fundamental cell biology leading to a new insight that puts us in a much better position to pioneer a foundation for new therapeutic approaches.”
Lindquist brought in two more collaborators late last year. Jean-Christophe Rochet at Purdue University tested the gene in midbrain neurons cultured from rat embryos, with the same results. University of Alabama researchers tried identical experiments in a roundworm model of Parkinson's disease that had been developed in the lab of Guy A. Caldwell, coordinator of an HHMI undergraduate science program.
“Lo and behold, it worked like a charm,” says Caldwell, whose work is also funded by the Michael J. Fox Foundation for Parkinson's Research. “It's a beautiful continuum going from a single cell to a mammalian system. It tells us this pathway is evolutionarily conserved.”
“Now we're off to the races,” says Lindquist. Participating researchers are following up on promising results in their respective animal models, exploring additional features of the biology in the more complex organisms and testing small molecules from the yeast drug screen as potential new drugs.