Parkinson's disease is a progressive neurological disorder estimated to affect almost 1 million people in the United States.

Signs and symptoms of Parkinson's include tremors - particularly in the hand or fingers - slowed movement, muscle rigidity, speech problems, and impaired balance and coordination.

While the precise causes of Parkinson's remain unclear, there is mounting evidence that a protein called alpha-synuclein (a-synuclein) plays a role.

Studies have shown that in the brains of Parkinson's patients, a-synuclein misfolds to form protein clumps called Lewy bodies, which accumulate in and destroy dopamine-producing cells of the substantia nigra - the brain region involved in movement.

The resulting reduction in dopamine - a neurotransmitter that helps regulate movement - leads to the impaired motor control characteristic of Parkinson's.

As such, researchers have been investigating ways to block a-synuclein accumulation as a strategy to prevent Parkinson's or slow its progression.

In the new study, co-author Jeremy Lee, of the University of Saskatchewan College of Medicine in Canada, and colleagues reveal the development of two caffeine-based compounds that they say could stop a-synuclein from clumping.
Two 'bifunctional dimers' stopped a-synuclein clump formation

According to Lee, the majority of drug compounds in development for Parkinson's have focused on increasing dopamine production of surviving nerve cells, "but this is effective only as long as there are still enough cells to do the job," he notes.

For their study - published in the journal ACS Chemical Neuroscience - Lee and team took a different approach; they set out to identify ways to protect dopamine-producing cells by halting the misfolding of a-synuclein.

Previous research has identified caffeine - a central nervous system stimulant present in coffee, tea, and cola - as having a protective effect against Parkinson's disease.

With this in mind, the team used a "caffeine scaffold" to create eight new compounds called "bifunctional dimers," which are molecules that connect two different substances that affect dopamine-producing cells.

Alongside caffeine, other compounds tested included nicotine, metformin (a drug used to treat diabetes), and aminoindan (an investigative drug similar to the Parkinson's drug rasagiline).

The team applied the dimers to a yeast model of Parkinson's disease, which is a yeast cell line that expresses a-synuclein-green fluorescent protein (AS-GFP).

From this, the researchers identified two caffeine-based compounds - referred to as C8-6-I and C8-6-N - that bind to a-synuclein and stop the protein misfolding and forming clumps.

At present, there is no cure for Parkinson's, only medications that can help patients manage symptoms of the disease. According to the authors, these new findings could pave the way to much-needed strategies to prevent or slow the disease.

    "Our results suggest these novel bifunctional dimers show promise in preventing the progression of Parkinson's disease." Jeremy Lee

Lee and colleagues now plan to test their novel compounds in mouse models of Parkinson's.