MIT researchers led by Susan Lindquist, a biology professor and
member of the Whitehead Institute for Biomedical Research, have
developed a way to protect neurons from degeneration and death in
animal studies of Parkinson's disease. The research, which focused
on a protein called alpha-synuclein, could lead to therapies for
human Parkinson's.
The disease's characteristic tremors and muscle rigidity are caused
by damage to and the death of neurons that use the neurotransmitter
dopamine to communicate with neighboring neurons. Alpha-synuclein
was known to be one of the main causes of that damage; large clumps
of it, in a misfolded form, are found in the brains of Parkinson's
patients. But researchers did not know what alpha-synuclein's normal
role is, why Parkinson's neurons accumulate too much of it, or how
it causes disease. Lindquist's team used a yeast model of
Parkinson's to study these questions.

Their research suggests that alpha-synuclein plays a role in the
process cells use to shuttle proteins between two internal
compartments in which critical refinements to proteins are made.
Before being shipped off to different parts of the cell, protein
strings often need to be cut or folded into three-dimensional
shapes, and sometimes groups such as carbohydrates must be added to
them. During these processes, the young proteins are sheltered
within protective lipid bubbles. The bubbles also protect the
neurons that produce dopamine from damage that can occur if too much
dopamine leaks out.

"Dopamine must be packaged in these membranes and sequestered from
[the insides of the cell], where it can cause oxidative damage,"
says Aaron Gitler, a postdoc in Lindquist's lab.

The researchers aren't sure exactly how buildup of misfolded alpha-­
synuclein disrupts protein trafficking but suspect it disturbs these
lipid ­bubbles. Gitler and Lindquist suggest that as a result,
neurons in Parkinson's patients are unprotected from their own
dopamine, which thus becomes toxic.

The scientists searched for a way to interfere with this effect.
Gene screening showed that activating the gene ypt1, which makes a
protein that helps shepherd other, freshly made proteins from one
part of the cell to another, did the job: the Parkinson's yeast
lived. Rab1, the equivalent shepherding protein in nematode, fly,
and rat neurons, also countered alpha-synuclein's toxicity. Rab1 did
not completely eliminate neuron death in some of these higher
organisms, but it was protective.

Much remains to be done, validation in tests on mice being the most
important step. But the Whitehead results have left researchers
optimistic about getting at the molecular details of Parkinson's. A
complex disease with few treatment options, Parkinson's affects
about a million people in the United States. This research
represents an important step toward understanding and curing it.

Katherine Bourzac, SM
November 14, 2006(Technology Review) -