Discovery May Lead to Better Treatments for Tremor, Other Movement Disorders

Two distinct proteins previously known to play key roles in the development of tremor associated with neurodegenerative diseases now have been found to interact directly, a discovery that might lead to new therapies for tremor-related movement disorders, including Parkinson’s disease.

The study with that finding, “LINGO1 is a regulatory subunit of large conductance, Ca²⁺-activated potassium channels”, was published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Parkinson’s hallmark motor symptoms include tremor, slowness of movement (bradykinesia), stiffness (rigidity), uncontrolled movements (dyskinesia) and poor balance.

These symptoms are a consequence of damage to neurons (nerve cells) in the brain’s cerebellum — an area that plays a key role in motor coordination and body balance.

People with Parkinson’s and essential tremor — a progressive movement disorder that causes involuntary shaking and is many times misdiagnosed as Parkinson’s — have higher amounts of a protein known as LINGO1, which has been implicated in movement control. People who have an extra copy of the LINGO1 gene also exhibit tremor, which further supports the idea that increased levels of the LINGO1 protein could play a key role in tremor.

Additionally, individuals with Parkinson’s and essential tremor have low levels of large conductance calcium-activated potassium (BK) ion channels within cerebellar neurons. These channels are present in the membrane of nerve cells and control the activation of neurons and smooth muscle — the tissue that lines the inside of blood vessels, internal organs and the digestive system.

Blocking or genetically deleting BK channels in mice has been found to induce tremor and movement disorders.

Now, researchers have used postmortem (autopsy) cerebellum samples of Parkinson’s patients and age-matched healthy controls to investigate the role and connection between LINGO1 and BK channels.

Researchers found that LINGO1 interacted with BK channels in the human cerebellum causing them to become inactive. This protein also reduced the expression of BK channels in the cell membrane of cells grown in the lab. However, BK channel protein expression was not altered in Parkinson’s patients’ cerebellar samples.

“Unfortunately, we were unable to ascertain if tremor was present in these deceased PD patients, and it therefore remains a possibility that the LINGO1 levels recorded in these patients were insufficient to down-regulate BK expression,” the researchers stated.

Importantly, the team found that, in cerebellar tissues from both Parkinson’s patients and age-matched controls, LINGO1 served as a regulatory subunit of BK channels.

“[T]hese two findings [referring to LINGO1 and BK’s role in the molecular mechanism of tremor] were previously thought to be unrelated. We put these two findings together and showed that LINGO1 inhibits the activity of BK channels, LINGO1 also reduces the expression of BK channels, the brains of Parkinson’s disease patients have higher levels of LINGO1, and LINGO1 is assembled with BK channels in the brains of Parkinson’s disease patients,” study author Brian Perrino, PhD, said in a press release. Perrino is associate professor, department of physiology and cell biology at the University of Nevada, Reno School of Medicine.

These results add to scientists’ understanding of the molecular mechanisms involved in neurodegenerative diseases associated with tremor. Importantly, they open the door for the development of new therapies that can block LINGO1’s interaction with BK channels and may potentially lessen motor symptoms associated with these disorders and improve patients’ quality of life.

“By bringing together an international team with complementary skills, this multi-disciplinary study promises to advance research and reveal new ways to help reduce the motor disorders associated with major disorders of the human brain,” said study author Mark Hollywood, PhD, professor, molecular physiology at the Dundalk Institute of Technology in Ireland.