Protecting Neurons from Parkinson's

New insights into the disease’s protein culprit

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.

Yeast Cells that model Parkinson’s disease. (Credit: Aaron Gitler)

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.

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