Parkinson’s progressively attacks motor functions, leading to lasting damage in movement and coordination. Researchers studying the primary causes of the disease have focused on mutations of the protein known as leucine-rich repeat kinase 2, or LRRK2.
Understanding how the protein disrupts normal functioning has been difficult due to a lack of information on its structure, according to a university statement. Efforts to decipher its architecture have included launching samples into space as a way of using microgravity conditions to help crystalize protein samples, but with no success.
The UCSD scientists produced the first visualizations of LRRK2 inside its natural cellular environment and the first high-resolution blueprint of the protein. They used these depictions to describe how LRRK2 binds to cellular tracks called microtubules and acts as a roadblock for motors that move along these tracks.
The findings are described in two research papers published in the journals Cell and Nature.
“These two papers take giant steps towards developing more effective therapeutics for Parkinson’s disease, which impacts so many lives,” said Biological Sciences Dean Kit Pogliano, a professor of molecular biology. “Combining cryo-electron microscopy with live cell imaging allows researchers to see proteins working inside cells and to more rapidly determine how potential drugs affect their function. This will accelerate drug discovery and provide new hope to those suffering from this debilitating disease.”
Researchers led by Elizabeth Villa and her colleagues used cryo- electron tomography, a type of cryo-electron microscopy, to view LRRK2 in its natural environment within cells and describe its structure at a level previously unseen.
In many cases, when researchers seek to determine a protein’s structure, they begin by isolating the protein outside of cells. When using cryo-EM, scientists freeze the molecules in a thin layer of ice, preserving their structure, and determine their structure at high resolution. Villa’s team images frozen cells that contain the molecules, taking pictures at different angles — somewhat like a CAT scan.
In the Nature study, co-senior authors Samara Reck-Peterson and Andres Leschziner took a deeper look at LRRK2’s structure and function and teamed up with Villa’s group to determine how LRRK2 interacts with cellular tracks.
Using cryo-EM, Leschziner’s team captured an atomic-level image of LRRK2’s structure. The structure comprised the business end of the protein — which includes the part that tags other proteins with phosphates. The locations of all major Parkinson’s disease-causing mutations are found in their structure.
Reck-Peterson’s team discovered that LRRK2 creates roadblocks that stop the transport of cargo inside the cell. It also showed that some drugs that target LRRK2 enhance this effect, while others diminish it.
While Leschziner and Reck-Peterson are not sure yet if roadblocks play a role in Parkinson’s disease, their findings already have implications for the design of therapeutic drugs that work by inhibiting LRRK2, researchers said.
–City News Service