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Protein Structure Reveals How Parkin Protects Neurons

Scientists have determined the structure of parkin, a protein that, when mutated, causes rare, inherited forms of Parkinson’s disease (PD). The discovery of parkin’s structure sheds light on how mutations in the parkin gene lead to PD, and how altering the protein might be a strategy for protecting neurons lost to PD. The study appears in the May 9 issue of Science.

Researchers already knew that the protein parkin helps to protect neurons. Parkin does this by preventing a lethal buildup of damaged mitochondria (structures that produce energy) in neurons. It labels the mitochondria, so the cell knows to destroy them. Meanwhile, when parkin is mutated, and not working, dysfunctional mitochondria accumulate and the cells die. More than 120 different mutations in the parkin gene have been associated with PD.

Researchers led by Kalle Gehring. Ph.D., at McGill University in Montreal, Canada used a standard technique known as X-ray crystallography to view the structure of normal parkin. To understand its mutations, they also created two variations of parkin: one altered in a way that they predicted would boost parkin’s effectiveness, and another changed to prevent parkin from doing its job. The new forms of parkin were labeled with a fluorescent dye and released into live cells, so the researchers could film their activity under a microscope.

Results

  • Parkin’s structure consists of five pieces that twist and hinge, something like a mechanical puzzle, to expose different surfaces and transform into different shapes as the protein goes about its work.
  • When the researchers made a mutation in an area called W403, parkin worked better by recognizing damaged mitochondria more quickly.
  • When researchers made a mutation in the area known as C431, parkin stopped working.

What Does It Mean?

Although very few people develop PD as a result of genetic mutations like the parkin gene, much can be learned about the biology of PD from these genes. The new study identified portions of the parkin molecule that are central to its role in protecting neurons. For example, it found that mutations that reduce parkin’s activity may lead to PD. 

Meanwhile, it proposes that changes that increase its activity may be used for neuroprotection – saving neurons in PD. The researchers found that in the lab, it was possible to alter a key part of the protein in a way that boosted its protective effects. By knowing the exact structure of parkin, scientists can begin to look for chemicals to enhance it, instead of having to randomly screen through thousands of compounds. 

Overall, these experiments provide a basis for further studies using chemicals that might enhance parkin’s activity, as a potential strategy for new PD therapies.

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Do you have more questions about genetics or treatments for Parkinson's? Contact us at (800) 457-6676 or info@pdf.org or use our free resources below.

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Reference: Trempe J-F, Sauvé V, Grenier K, Seirafi M, Tang MY, Ménade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K (2013) Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation. Science. Ahead of Print. DOI: 10.1126/science.1237908 http://dx.doi.org/10.1126/science.1237908

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Source Date: Jun 13 2013