One Nature and one Cell paper revealed the mechanism of action of the protein LRRK2 associated with Parkinson's disease.

!--, August 26, 2020 // --- An elusive protein that many believe is key to a comprehensive understanding of the causes of hereditary Parkinson's disease is now more clearly in the spotlight.
, which affects millions of people around the world, is a neurological disease that gradually attacks motor function and causes lasting damage in areas such as movement and coordination.
studying the main causes of the disease have focused on mutations in a protein called leucine-rich repeat kinase 2 (leucine-rich repeat kinase 2, LRRK2).
it has been difficult to understand how LRRK2 disrupts normal function due to a lack of information about the protein's structure.
given that LRRK2 is a major drug target, efforts to decipher the structure of LRRK2 even include sending samples into space to help protein samples crystallize using microgravity conditions, but without success.
now, researchers from research institutions such as the University of California, San Diego, have used cutting-edge technology to create the first visualizations of LRRK2 in its natural cellular environment, as well as the protein's first high-resolution blueprint.
they used these diagrams to describe how LRRK2 binds to cellular orbits called microtuposals and act as a roadblock to molecular motors moving along those orbits.
results were published online on August 19, 2020 and August 11, 2020 in the Journal of Nature and cell under the titles "Structure of LRRK2 in Parkinson's disease and model for microtubule interaction" and "The Situ Structure of Parkinson's Disease-Linked LRRK2".
photo from Reck-Peterson and Leschziner Labs, UC San Diego.
, president of the School of Biological Sciences at the University of California, San Diego, said, "Given that Parkinson's disease affects many people's lives, these two papers are a huge step toward developing more effective treatments for Parkinson's disease."
combining cryo-EM with live cell imaging, the researchers were able to observe the mechanism of the protein's action within the cell and more quickly determine how potential drugs affect its function.
will speed up drug discovery and offer new hope to people with this debilitating disease.
"LRRK2: A key therapeutic target for Parkinson's disease as a kinase that adds chemical labels of phosphate to other proteins, affecting their function.
LRRK2 mutation is the main cause of hereditary Parkinson's disease, but scientists don't fully understand the function of the enzyme in normal or diseased conditions.
people have been looking hard for answers to these questions, especially since kinase is one of the most sophisticated drug treatment targets.
since the LRRK2 gene was first cloned in 2004, great efforts have been made to target the treatment of Parkinson's disease.
, a world-renowned kinase authority, recognizes that the expertise of the University of California, San Diego is well suited to solving this problem.
, with the support of the Michael Fox Foundation, an international team, including researchers at the University of California, San Diego, began using new technologies to study LRRK2.
LRRK2's cell blueprint on the micro tube, as described in this Cell paper, researchers at the University of California, San Diego, led by Dr. Elizabeth Villa and colleagues, used a new breakthrough technique called cryo-electron tomography(cryo-ET), a new model of cryo-EM, to observe LRRK2 in the natural environment of the cell and describe its structure at a level not previously observed.
, when people try to determine the structure of a protein, they first isolate it outside the cell.
when using cryo-EM, scientists freeze protein molecules in thin ice, preserve their structure, and determine their structure at high resolution.
And Villa's team imaged frozen cells containing the protein molecules under study, taking pictures from different angles, a bit like CAT scans.
open the bonn and look at frozen molecules that interact inside cells at different locations in the cell," said Veilla.
we use electrons and ion beams, like a lightsaber, to blow away parts of the cell.
we left a window in the middle with protein molecules that we were interested in observing.
also used optical microscopes to find protein molecules in cells and advanced computational modeling tools to develop high-resolution composite models of LRRK2 mutants.
their data revealed the binding of LRRK2 to a cellular highway called micro tubes, decorating microcontrols with surprising rules and unexpected geometry, and predicting that LRRK2's kinase activity is similar to the known "overspeed" state in Parkinson's disease.
, "This powerful combination of new technologies was first applied in this study and makes it possible to observe the structure of the LRRK2 mutant for the first time, in addition to its cellular environment," said Veilla.
we know, this is the highest resolution structure of human proteins previously measured in cells using traditional bio-chemical tools.
we are bringing structures into cell biology.
"Molecular Blueprints for LRRK2 In order to understand how LRRK2 works at the chemical level and design treatments, higher resolution structures are needed to reveal the location of atoms and how they interact with potential drugs."
in this Nature paper, co-authors Samara Reck-Peterson and Dr. Andres Leschziner delved deeper into the structure and function of LRRK2 and worked with the Villa team to determine how LRRK2 interacts with micro tubes.
!--/ewebeditor:page--!--ewebeditor:page title"--Leschziner's team captured the most detailed images of the LRRK2 structure to date at atomic levels using cryo-EM.
, a professor at Goethe-Insted University in Frankfurt, Germany, and his team also played an important role in deciding how to make LRRK2 easy to do structural research.
results include the business side of the protein -- including the use of phosphate groups to label parts of other proteins.
the location of all major Parkinson's disease-caused mutations in this structure.
, the Leschziner team combined their structure with Villa's and came up with a model that explains how LRRK2 binds to micro tubes.
Leschziner said, "You can think of the kinase part of LRRK2 as a bit like a bean eater, it can be open or it can be closed."
our modeling shows that when binding to a micro tube, the kinase needs to be closed, suggesting that the shape of the kinase may regulate the binding of LRRK2 to the micro tube.
with Reck-Peterson Labs, we decided to test the model directly.
"LRRK2 is a roadblock for molecular motors Reck-Peterson specializes in studying microcontrol.
she and her team are interested in molecular motors that transport goods along micro tubes and how defects in such transport can lead to neurodegenerative and neurodegenerative diseases in humans.
Reck-Peterson and her team wanted to know if LRRK2's interaction with micro tubes could cause damage to molecular machines that move on micro tubes and transport important cargo to cells.
her team found that LRRK2 would create roadblocks to stop these molecular machines from working.
also shown that some drugs targeting LRRK2 kinases enhance this effect, while others weaken it.
While Leschziner and Reck-Peterson are not sure whether these barricades play a role in Parkinson's disease, their findings have had an impact on the design of therapeutic drugs that inhibit the effects of LRRK2.
their study suggests that kinase inhibitors that shut down the LRRK2 kinase domain may have harmful effects that block the movement of molecular motors.
re not yet clear what role LRRK2-microtranscing plays in Parkinson's disease," said Reck-Peterson, a professor at the hospital.
we now have a cellular blueprint and a molecular blueprint, which is what is needed to understand the role of LRRK2 and fine-tune therapeutic drugs for LRRK2.
"(Bioon.com) Reference: 1.C. K. Deniston et al. Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. Nature, 2020, doi:10.1038/s41586-020-2673-2.2.Reika Watanabe et al. The In Situ Structure of Parkinson's Disease-Linked LRRK2. Cell, 2020, doi:10.1016/j.cell.2020.08.004.3.Leading-edge Technology Unmasks Protein Linked to Parkinson's Disease.