Early research in mice could be getting closer to the roots of what causes Parkinson’s disease.

A “pathological” form of a common brain protein, alpha-synuclein, could play a role in the death of dopamine-rich brain cells, according to a team at Johns Hopkins School of Medicine in Baltimore.

It’s this steady loss of dopamine cells that’s a hallmark of Parkinson’s, researchers explained.

“Parkinson’s disease has major impacts on quality of life for patients, but also for their caretakers and loved ones. We hope that research like this will provide mechanistic, molecular-based therapies that can actually slow or halt the progression of Parkinson’s disease,” study lead author Dr. Ted Dawson said in a Hopkins news release. He’s a professor of neurology at Hopkins and director of the university’s Institute for Cell Engineering.

Dopamine is a crucial chemical messenger in the brain, but as Parkinson’s disease progresses, more dopamine-laden neurons are lost to the illness. This results in a steady worsening of motor skills and cognition. 

Parkinson’s patients typically receive drugs such as L-dopa to replace lost dopamine, but benefits wear off over time.

Alpha-synuclein has long been linked to a loss of dopamine-rich brain cells, but its exact role has been unclear.

In the new study, Dawson’s team used high-tech methods to identify other proteins whose interactions with alpha-synuclein might lead to brain cell death.

In the lab and in mice, they spotted 100 candidates. Most played roles in processes cells use to produce new proteins. 

When a “bad” form of alpha-synuclein linked up with another cellular protein called tuberous sclerosis complex 2 (TSC2), this combo allows a third protein, called mTOR, to run amuck in cells.

mTOR boosts protein production inside cells, the Hopkins team explained, but if mTOR’s activity becomes excessive, brain cells can die.  

Just how that happens still isn’t clear — maybe the proteins gum up the works inside cells, or maybe certain proteins might become toxic if overproduced.

However, giving mice with a Parkinson’s-like condition an mTOR-targeted drug called rapamycin halted this excessive cellular protein production, the researchers found.  

Treated in this way, the mice also began to lose the “slow, halting movements” that are so characteristic of Parkinson’s, Dawson’s group said.

Rapamycin is already used to fight cancers or the organ rejection that can arise after transplant. It comes with serious side effects, however. 

So, Dawson’s team hopes that a rapamycin-like drug might someday be developed that can keep dopamine-rich brain cells alive, with fewer systemic side effects for patients. 

The findings were published recently in Science Translational Medicine.

More information

Find out more about Parkinson’s disease at the Michael J. Fox Foundation.

SOURCE: Johns Hopkins University School of Medicine, Dec. 18, 2023

Source: HealthDay

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