Parkinson'S Disease Process May Be Curtailed By Regenerative Processes In
Yeast, Fruit Flies



Whitehead researcher leads multi-institutional team.
Yeast might not be the most obvious experimental model for neurodegenerative
diseases. For one thing, yeast cells don't have brains.
But these single-celled creatures get sick and die from the same toxic culprit
that mucks up dopamine-producing neurons in Parkinson's disease. Now, a
multi-institutional team led by Susan Lindquist, MIT biology professor and
Whitehead Institute member, has found a way to reverse the damage in yeast.
Even better, the team confirmed the same defect and cure in
dopamine-producing neurons of fruit flies, roundworms and rats.
The findings reveal how simple yeast may speed up the search for new
therapeutics for complex brain diseases that are hard to study in people. "We
put a human gene into an organism that separated from us in evolution one
billion years ago, and we found the same biochemical activity," says
Lindquist, who is also a Howard Hughes Medical Institute investigator. "This
is a new way to understand the biology and a potential mechanism for
discovering drugs."
Three years ago, researchers in Lindquist's lab at the Whitehead Institute
showed how yeast can serve as "living test tubes" by supplementing them with
the gene encoding the human protein alpha-synuclein-a major contributor to
compromised brain function in people with Parkinson's disease. One copy of
the gene didn't hurt the yeast, but two copies proved fatal. "That's when we
decided to use the yeast for genetics and for drug screening," says
Lindquist.
In work reported in the July 21 issue of Science, Lindquist and her colleagues
investigated whether extra amounts of any yeast gene could offset the effects
of excess alpha-synuclein. They set about testing 5,000 yeast genes one by
one.
The sought-after response emerged after they had tested a third of the genes
in the yeast genome. Yeast bogged down by alpha-synuclein perked up when they
had extra copies of genes associated with the movement of proteins from one
cellular compartment to another. More specifically, these genes affect the
flow of tiny fatty bubbles known as vesicles from the endoplasmic reticulum
(ER), where newly made proteins are customized for special duties, to the
Golgi complex, where the proteins are further modified, repackaged and
addressed for delivery. An extra copy of one particular gene rescued the
yeast from alpha-synuclein overload--and, later, its counterpart did the same
for roundworms, fruit flies and rat neurons.
"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.
"Lo and behold, it worked like a charm," says Caldwell. "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.
By Massachusetts Institute of Technology

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