Researchers at Weill Cornell Medicine have identified how the Parkinson's-related protein LRRK2 shifts between inactive and active forms, revealing structural changes that enable certain mutations to make the protein overactive. The findings, published Aug. 10 in Cell, may inform new approaches for developing targeted therapies for Parkinson's disease.
Mutations causing LRRK2 to become abnormally active are among the most common genetic causes of Parkinson's disease. Some individuals with Parkinson's also show elevated LRRK2 activity even without these mutations. Understanding how LRRK2 becomes overactive is considered important because it is a leading target for treatments aiming to slow the progression of the disease.
The research team used electron microscopy and biochemistry to capture LRRK2 in different states, enabling them to determine how the protein toggles between its active and inactive forms. "With at least four ongoing clinical trials, LRRK2 is considered one of the most promising targets for Parkinson's therapeutics," said Dr. Samara Reck-Peterson, chair and professor of biochemistry and biophysics at Weill Cornell Medicine, who co-led the investigation. "Our work provides a platform for identifying molecules that promote the formation of one configuration or the other, which could help researchers design drugs that selectively control LRRK2 activity."
LRRK2 is composed of seven domains; some act as grips helping it attach inside cells while two domains provide enzymatic activities—one binds GTP (a molecular switch) and another acts as a kinase adding phosphate groups to proteins. Increased levels of these modifications are associated with Parkinson’s disease.
By examining 16 different structures—some loaded with GTP or GDP—the team reconstructed how structural changes turn LRRK2 on or off. When GDP is present, key domains block kinase activity; when GDP leaves and GTP binds, an active conformation exposes this site.
"Our observations uncover the rules for how to control whether LRRK2 is active or not, and since hyperactivity is linked to Parkinson's, this provides a roadmap for new therapeutics," said Reck-Peterson.
The study also showed that different mutations increase kinase activity through distinct mechanisms: some directly affect the kinase site while others act from distant regions by increasing time spent in an active shape rather than speeding up its function overall.
"Our work gives medicinal chemists the blueprint to design drugs that target the on/off switch in LRRK2 rather than acting directly on the kinase," said Dr. Leschziner.
