How proteins LRRK2, Rab29 work together to drive Parkinson’s: Study
Data may open avenues for designing treatments for late-onset Parkinson’s
Scientists have uncovered the complex structure and interplay of two proteins, called LRRK2 and Rab29, that are implicated in late-onset Parkinson’s disease.
Specifically, they found LRRK2 is recruited to the membranes of cells by forming a complex with Rab29, causing LRRK2 to undergo changes in its structure and adopting an active state.
A technique called cryo-electron microscopy was used, which allowed researchers to see the detailed structures of proteins and to understand how they move or change as the proteins perform their functions.
Understanding these structural conformations offers a molecular-scale map that can help trace how the different mutations that cause Parkinson’s affect function within the protein complex, perhaps opening new avenues for designing medicines to treat Parkinson’s.
“These structures provide much-needed insights for medicinal chemists to design novel inhibitors against LRRK2 for Parkinson’s treatment,” Ji Sun, PhD, who led the study at St. Jude Children’s Research Hospital in Memphis, said in a press release.
The study, “Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2,” was published in Science as a collaborative effort between Sun’s team and researchers at the University of Dundee in the U.K.
Mutations affecting LRRK protein can cause late-onset Parkinson’s
Mutations in the gene coding for LRRK2 are common genetic causes of late-onset Parkinson’s, where symptoms appear after the age of 50. These mutations result in aberrant activity of LRRK2, which is thought to stop lysosomes — the recycling centers of cells — from breaking down toxic material within nerve cells.
Rab29, a protein that regulates molecular trafficking within cells, modulates the activity of LRRK2. How Rab29 and LRRK2 may work together to cause Parkinson’s, however, remains unclear.
Earlier work by Sun’s team established how LRRK2 folds when it is in its inactive state. Proteins can exist in active or inactive states in cells. Sometimes, a protein needs to attach to another protein to undergo structural changes and shift from an inactive state to an active one.
However, studying LRRK2 is challenging because it is a large protein and it is present in only very small amounts on cells’ membranes, where it forms oligomers (molecules that consist of a few repeating units). “Those are the versions that are active and functional,” Sun said.
Using cryo-electron microscopy, the researchers have now determined the structures of LRRK2 in its active form when bound to Rab29, a membrane-associated protein thought to help shuttle LRRK2 to specific locations within cells.
This included the structures of a monomer (one pair) and dimer (two pairs), but also an unexpected tetramer (four pairs) where LRRK2 exists in both active and inactive states upon recruitment by Rab29 to the cell membrane.
“When Rab29 recruits LRRK2 to the membrane, the local concentration of LRRK2 increases. This then facilitates the transition to tetramer, wherein LRRK2 becomes active,” Sun said.
First high-resolution LRRK2 structures captured in its active state
“We are really excited about the structural findings, as they represent the first high-resolution LRRK2 structures captured in its active state,” said Hanwen Zhu, PhD, who is the study’s first author.
Mutations that cause Parkinson’s tend to favor the active state, meaning they provide new interactions or disrupt existing ones within the inactive state. “The effects of the mutations can be visualized beautifully in our structures; it’s very well explained,” Sun said.
The active core of the tetramer formed by four pairs of LRRK2 and Rab29 looks very similar to the active state that can be trapped by Denali Therapeutics’ DNL201, an experimental small molecule that blocks the activity of LRRK2.
In two Phase 1 clinical studies (NCT04551534 and NCT03710707), DNL201, given by mouth once or twice daily, was found to be safe and well tolerated by healthy volunteers and people with Parkinson’s with or without mutations in the LRRK2 gene.
“Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson’s disease treatment,” the researchers wrote.