Traffic report

Clearing protein jams in neurons can reverse Parkinson’s symptoms in animals

Few things put us in a worse mood than sitting in traffic. But when a similar kind of traffic jam occurs in our neurons, the consequences are far more dire. Parkinson’s disease can set in, and when it does, there’s no turning back.

In general, statistics for neurological disorders are grim. More than a million Americans suffer from Parkinson’s disease alone—a number that is expected to soar over the next few decades as the population ages. No current therapies alter the fundamental clinical course of the condition.

A recent advance in our understanding of this condition, however, makes researchers a bit more optimistic about our prospects for eventually treating patients more effectively.

Scientists at Whitehead Institute, in collaboration with colleagues at several research centers, including the University of Missouri’s School of Biological Sciences, have identified a key biological thoroughfare that, when backed up, causes Parkinson’s symptoms.

Even more importantly, they have figured out how to repair the traffic flow and restore normal neurological function in certain animal models.

“For the first time we’ve been able to repair dopaminergic neurons, the specific cells that are damaged in Parkinson’s disease,” says Whitehead Member and Howard Hughes Medical Institute Investigator Susan Lindquist, senior author in the paper appearing last June in Science.

This research began back in 2003, when Tiago Outeiro, a graduate student in Lindquist’s lab, described using yeast cells as “living test tubes” in which to study Parkinson’s. A Science paper reported that when a Parkinson’s-related protein called alpha-synuclein was over-expressed in these cells, clumps of misshapen proteins gathered near the membrane, and in many cases the cells either became sick or died.

This paper was of particular interest because the findings were arrived at via yeast cells, a rather unlikely model organism for brain disease.

Aaron Gitler and Anil Cashikar, postdoctoral researchers in the Lindquist lab, decided to follow up by asking a simple question: Is it possible to rescue these cells when an overexpression of alpha-synuclein would normally make them sick?

They began with an array of yeast cells in which each cell over-expressed one particular gene. This array, prepared by scientists at the Harvard Institute of Proteomics, covers the entire yeast genome. All cells were also infected with alpha-synuclein. They reasoned that if they identified genes whose over-expression rescued a cell, that would tell them something about how alpha-synuclein made the cell sick in the first place.

Most of the proteins that they identified pointed to a pathway that involves two cellular organelles, the endoplasmic reticulum (ER) and the Golgi complex. The ER is the cell’s protein factory, where proteins assume their requisite shapes. Once a protein has properly folded, it is trafficked over to the Golgi, where it is fine-tuned and further prepared for its designated task.

Working with Antony Cooper from the University of Missouri, Kansas City, Lindquist’s team demonstrated that when alpha-synuclein becomes mutated and clumps at the cell surface, it drags away a protein that eases transport between the ER and the Golgi.

“This protein is the traffic cop for the ER-Golgi route,” says Lindquist. “Once it’s gone, the molecules start backing up at the ER.” It is this cellular traffic jam that causes cell death.

This isn’t just a general toxic effect caused by any misfolded protein. It is specific to alpha-synuclein, the protein associated with Parkinson’s disease.

Repairing neurons

“All this was done in yeast,” says Gitler. “Our next goal was to find what this told us about actual neurons.”

If mutations of alpha-synuclein dragged the ER-Golgi protein away from doing its job of directing traffic, as the yeast research indicated, then cell death might be averted simply by increasing the levels of this transport protein—that is, by adding extra traffic cops to the scene.

Working with colleagues at the University of Pennsylvania, the University of Alabama, and Purdue University, the consortium tested this hypothesis in the fruit fly, C. elegans worm and in neurons culled from rats—all of which had alpha-synuclein-induced Parkinson’s symptoms. In every case, symptoms were reversed by increasing levels of the trafficking protein.

“We tried this a number of different ways, from creating transgenic animals that naturally over-expressed this protein, to injecting a copy of the gene for this transport protein into the neurons through a gene-therapy technique,” says Gitler. “The results were the same. Cell death ceased, and the neurons were restored to normal health.”

“Protein folding problems are universal, so we hoped we could use these simple model organisms to study something as deeply complex as neurodegenerative disease,” says Lindquist, who is also a professor of biology at MIT. “Most people thought we were crazy. But we now not only have made progress in understanding this dreadful disease, but we have a new platform for screening pharmaceuticals.”

“This gives a whole new direction for understanding what’s been going wrong in these patients, and for considering much better strategies for treating people,” says Cooper.