Summary

Armed with the first detailed structure of a key enzyme involved in the neurological disorder, researchers begin hunting for drugs that reduce its activity.

Some cases of Parkinson’s disease can be attributed to a protein called LRRK2. Scientists determined the structure of a key section of LRRK2 (above), which contains a common target for drugs (orange, center). Credit: Colin Deniston et al./Nature 2020

A new 3-D model of a protein implicated in Parkinson’s disease hints at what goes wrong in the neurological disorder — and how scientists might be able to fix it.

Cell biologist Samara Reck-Peterson and her collaborator Andres Leschziner reported the cryo-electron microscopy structure of a key part of this protein on August 19, 2020, in the journal Nature.

“Ever since it became clear that this protein contained a good target for drugs, pharmaceutical companies, biotech, and academic labs began trying to solve the structure of it,” says Reck-Peterson, a Howard Hughes Medical Institute Investigator at the University of California, San Diego (UCSD). “This is the first time anyone’s been able to do so at such a high resolution.”

With the detailed model the Leschziner group assembled, Reck-Peterson and Leschziner identified a potential new route for developing treatments that slow disease progression – something that is not currently possible.

Mysterious molecular origins

More than 4 million people worldwide suffer from Parkinson’s disease, a neurological disorder that can first show up as trembling or difficulty moving. Over time, symptoms worsen, interfering with patients’ ability to walk, talk, and eat. While doctors can treat these symptoms, they have no way of halting the damage to and death of neurons that causes Parkinson’s.

A key component of LRRK2 (dark and light orange) hinges together, opening and closing like Pac-Man’s mouth. When closed, LRRK2 can form roadblocks on microtubule highways that could play a role in Parkinson’s disease. Credit: Colin Deniston et al./Nature 2020

About 15 percent of people diagnosed with the disease have a family history of Parkinson’s, but most cases arise sporadically. Research has pointed to changes in a protein called LRRK2 as one cause for both types of the disease, although scientists haven’t fully understood its role.

Normally, LRRK2 is found in several places within cells, including, in some cases, on microtubules – tiny tubes that serve as a molecular highway system for cellular cargo. LRRK2 that contains Parkinson’s mutations can glom on to microtubules much more frequently than usual.

As part of a collaborative effort to study the protein’s activity, Reck-Peterson’s UCSD colleagues, including Leschziner and Elizabeth Villa, examined the structure of LRRK2, which inlcudes a region known as a kinase. Kinases control much of the molecular action that occurs within the body. The scientists suspected LRRK2’s kinase was crucial for interacting with microtubules. In related research recently published in the journal Cell, Villa showed how LRRK2 wraps around these tiny cellular roadways.

Dario Alessi, a biochemist at the University of Dundee who was not involved in the research, describes the teams’ effort to resolve the kinase structure as a technical “tour de force,” saying, “it shows us with new eyes how the kinase functions.” Most important, however, are the implications for drug development, he says.

Open and shut

Because kinases control processes disrupted in a host of diseases, including cancer, diabetes, and inflammation, researchers have already developed many drugs to alter their activity, Alessi says. In 2004, when scientists determined the genetic sequence of LRRK2, they learned it contained one of these relatively easy-to-access targets.

Reck-Peterson and her colleagues discovered that the shape of LRKK2’s kinase likely changes depending on where the protein is found. When not on microtubules, the kinase’s two halves relax away from one another. “Think of Pac-Man with his mouth open,” Reck-Peterson says. When on the microtubules, Pac-Man’s mouth closes.

Many LRRK2 kinases with this closed Pac-Man shape can link together to form a chain that wraps around microtubules, the researchers report. In follow-up experiments, Reck-Peterson showed that this chain becomes a roadblock – like a concrete barricade, it brings traffic along the microtubule highway to a halt.

She and colleagues then looked for drugs that could manipulate the kinase to keep LRRK2 off the microtubules.

LRRK2 molecules

A new direction for treatments?

The existing drugs that inhibit LRRK2’s kinase fall into two general categories, Reck-Peterson says. “Some drugs wedge into Pac-Man’s mouth, keeping it open, while others lock the mouth closed.” In experiments, only drugs that trapped the kinase in an open shape allowed cellular traffic to continue moving along the microtubule highways. That’s probably because keeping the Pac-Man open loosened or released the LRRK2 roadblocks, she says. 

It is not yet clear, however, that these roadblocks contribute to the neurological damage seen in Parkinson’s disease. If future studies confirm their role, this class of kinase-opening drugs is likely worth pursuing for potential treatments, Alessi says.

Pharmaceutical companies are already investigating the use of kinase-targeting drugs for Parkinson’s  – but those now in clinical trials lock LRRK2’s kinase closed. That strategy may need to change, he says. “I think companies will be scratching their heads, thinking about developing inhibitors that leave LRRK2 off microtubules.”

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Citation

Colin K. Deniston et al. “Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction.” Nature. Published online August 19, 2020. doi: 10.1038/s41586-020-2673-2

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