Rewriting Life

Protecting Neurons from Parkinson's Disease

Insights into the disease’s protein culprit could lead to human therapies.

Researchers have uncovered a way to protect neurons from degeneration and death in animal models of Parkinson’s disease. Although scientists have known which protein is the main culprit in Parkinson’s nerve damage, both the protein’s normal function and details of its harmful effects have remained a mystery. Now a recent genetic study has uncovered some of this protein’s mysterious activities, and researchers have used what they learned to save neurons affected by the disease. The research could lead to targeted therapies for human Parkinson’s.

Yeast cells have been engineered to grow fluorescently labelled clumps (brighter green areas) of a human Parkinson’s protein. The cells are being used to search for genes that protect against the disease. (Courtesy of Aaron Gitler, Whitehead Institute.)

A team of researchers, led by Susan Lindquist, an MIT biology professor and member of the Whitehead Institute for Biomedical Research, where the study was done, performed genetic screens in a yeast model to illuminate the role of the protein synuclein, which is present in large clumps in neurons affected by Parkinson’s. The disease’s characteristic tremors and muscle rigidity are caused by damage and death to a class of neurons that produce the neurotransmitter dopamine. Lindquist’s lab engineered yeast that make synuclein and that can act as a model for these neurons. Using these yeast, they screened large libraries of genes in search of those that counteracted synuclein’s toxicity.

Out of several candidate genes, one stood out: a gene involved in protein trafficking. Linquist’s group discovered that large amounts of misfolded synuclein seem to interfere with cells’ ability to shuttle proteins between two organelles. And these organelles play a critical role in refining proteins: before being shipped off to different parts of the cell, protein strings often need to be cut, folded into three-dimensional shapes, or have additional groups such as carbohydrates added. During this process, they are sheltered within a protective lipid bubble.

The researchers aren’t sure exactly how synuclein disrupts protein trafficking, but they suspect it disturbs these protective bubbles. “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 post-doc in Lindquist’s lab. He and Lindquist suggest that one reason dopamine-producing neurons die in Parkinson’s patients is that synuclein leaves them unprotected.

Using their gene-screening technique, Whitehead scientists found a way to interfere with overactive synuclein. When they activated the gene Rab 1, whose product is involved in shepherding freshly made proteins from one part of the cell to another, the Parkinson’s yeast lived. The equivalent protein in nematode, fly, and rat neurons also countered synuclein’s toxicity, suggesting that this protein helps neurons to overcome synuclein’s block in protein processing.

“The findings hold up nicely,” says Darren Moore, assistant professor at Johns Hopkins University School of Medicine’s Institute for Cell Engineering. The gene may also prove to be protective in human Parkinson’s. “Potentially drugs or gene therapy could be used to increase protein trafficking in human neurons,” says Gitler.

Unlike those of many other proteins associated with diseases, the harmful effects of synuclein are not due to a mutation, but to misfolding and large quantities of the protein. Lindquist’s and Gitler’s research suggests that synuclein plays a normal role in the trafficking of freshly made proteins, but that things go awry when neurons make too much. The idea that synuclein’s normal function is similar to its actions in Parkinson’s “is really interesting and in some ways fits well with the observation that duplications or triplications in its gene can lead to the disease,” says Steven Finkbeiner, associate investigator at the University of California at San Francisco’s Gladstone Institute of Neurological Disease.

Gitler says the study showed that in yeast, protein trafficking problems are the first sign of Parkinson’s. But that doesn’t mean trafficking is the only important factor in the human disease. In fact, in the other organisms they studied, increased amounts of protective Rab1 decreased but didn’t eliminate neuron death. Rab1 was only one of several protective genes the Whitehead researchers found, however, and they have not yet tested all of about 6,000 yeast genes.

Much remains to be done, in particular, validation in a mouse model. But the Whitehead results have left researchers optimistic about the prospects of getting at the molecular details of Parkinson’s – a complex disease with few treatment options. At least 500,000 people in the United States suffer from Parkinson’s. For them, this research represents an important step toward understanding and curing the disease.

Tech Obsessive?
Become an Insider to get the story behind the story — and before anyone else.

Subscribe today

Uh oh–you've read all of your free articles for this month.

Insider Premium
$179.95/yr US PRICE

More from Rewriting Life

Reprogramming our bodies to make us healthier.

Want more award-winning journalism? Subscribe and become an Insider.
  • Insider Premium {! insider.prices.premium !}*

    {! insider.display.menuOptionsLabel !}

    Our award winning magazine, unlimited access to our story archive, special discounts to MIT Technology Review Events, and exclusive content.

    See details+

    What's Included

    Bimonthly home delivery and unlimited 24/7 access to MIT Technology Review’s website.

    The Download. Our daily newsletter of what's important in technology and innovation.

    Access to the Magazine archive. Over 24,000 articles going back to 1899 at your fingertips.

    Special Discounts to select partner offerings

    Discount to MIT Technology Review events

    Ad-free web experience

    First Look. Exclusive early access to stories.

    Insider Conversations. Listen in as our editors talk to innovators from around the world.

  • Insider Plus {! insider.prices.plus !}* Best Value

    {! insider.display.menuOptionsLabel !}

    Everything included in Insider Basic, plus ad-free web experience, select discounts to partner offerings and MIT Technology Review events

    See details+

    What's Included

    Bimonthly home delivery and unlimited 24/7 access to MIT Technology Review’s website.

    The Download. Our daily newsletter of what's important in technology and innovation.

    Access to the Magazine archive. Over 24,000 articles going back to 1899 at your fingertips.

    Special Discounts to select partner offerings

    Discount to MIT Technology Review events

    Ad-free web experience

  • Insider Basic {! insider.prices.basic !}*

    {! insider.display.menuOptionsLabel !}

    Six issues of our award winning magazine and daily delivery of The Download, our newsletter of what’s important in technology and innovation.

    See details+

    What's Included

    Bimonthly home delivery and unlimited 24/7 access to MIT Technology Review’s website.

    The Download. Our daily newsletter of what's important in technology and innovation.

/
You've read all of your free articles this month. This is your last free article this month. You've read of free articles this month. or  for unlimited online access.