Brain chemical lost in Parkinson’s may contribute to its own demise

BY  LAURA SANDERS  SEPTEMBER 7, 2017

In a hopeful note, treating dopamine-producing nerve cells with antioxidants lessened damage

DOPAMINE DAMAGE  In Parkinson's disease, a dangerous form of the chemical messenger dopamine may help destroy the nerve cells that produce it, a new study suggests.

The brain chemical missing in Parkinson’s disease may have a hand in its own death. 

Dopamine, the neurotransmitter that helps keep body movements fluid, can kick off a toxic

 chain reaction that ultimately kills the nerve cells that make it, a new study suggests.

By studying lab dishes of human nerve cells, or neurons, derived from Parkinson’s patients,

 researchers found that a harmful form of dopamine can inflict damage on cells in multiple

 ways. The result, published online September 7 in Science, “brings multiple pieces of the 

puzzle together,” says neuroscientist Teresa Hastings of the University of Pittsburgh School 

of Medicine.

The finding also hints at a potential treatment for the estimated 10 million people worldwide 

with Parkinson’s: Less cellular damage occurred when some of the neurons were treated 

early on with antioxidants, molecules that can scoop up harmful chemicals inside cells.

Study coauthor Dimitri Krainc, a neurologist and neuroscientist at Northwestern University 

Feinberg School of Medicine in Chicago, and colleagues took skin biopsies from healthy 

people and people with one of two types of Parkinson’s disease, inherited or spontaneously 

arising. The researchers then coaxed these skin cells into becoming dopamine-producing 

neurons. These cells were similar to those found in the substantia nigra, the movement-

related region of the brain that degenerates in Parkinson’s.  

DARK MARK  Dark spots of neuromelanin (arrow) appear inside 90-day-old cells derived from a person carrying a Parkinson’s-related mutation. These deposits, visualized by electron microscopy, contain a damaging form of dopamine.

After neurons carrying a mutation that causes the inherited form of Parkinson’s had grown

in a dish for 70 days, the researchers noticed some worrisome changes in the cells’

mitochondria. Levels of a harmful form of dopamine known as oxidized dopamine began

rising in these energy-producing organelles, reaching high levels by day 150. Neurons

derived from people with the more common, sporadic form of Parkinson’s showed a

similar increase but later, beginning at day 150. Cells derived from healthy people didn’t

accumulate oxidized dopamine.

This dangerous form of dopamine seemed to kick off other types of cellular trouble.

Defects in the cells’ lysosomes, cellular cleanup machines, soon followed. So did the

accumulation of a protein called alpha-synuclein, which is known to play a big role in

Parkinson’s disease.

Those findings are “direct experimental evidence from human cells that the very chemical

lost in Parkinson’s disease contributes to its own demise,” says analytical neurochemist

Dominic Hare, of the University of Technology Sydney. Because these cells churn out

dopamine, they are more susceptible to dopamine’s potential destructive forces, he says.

When researchers treated neurons carrying a mutation that causes inherited Parkinson’s

with several different types of antioxidants, the damage was lessened. To work in people,

 antioxidants would need to cross the blood-brain barrier, a difficult task, and reach the

mitochondria in the brain. And this would need to happen early, probably even before

symptoms appear, Krainc says.

“Without this human model, we would not have been able to untangle the pathway,” Krainc

says. In dishes of mouse neurons with Parkinson’s-related mutations, dopamine didn’t kick

off the same toxic cascade, a difference that might be due to human neurons containing

more dopamine than mice neurons. Dopamine-producing neurons in mice and people

“have some very fundamental differences,” Krainc says. And those differences might help

explain why discoveries in mice haven’t translated to treatments for people with

Parkinson’s, he says.

Over the past few decades, scientists have been accumulating evidence that oxidized

 dopamine can contribute to Parkinson’s disease, Hastings says. Given that knowledge,

the new results are expected, she says, but still welcome confirmation of the idea.

These toxic cellular events occurred in lab dishes, not actual brains. “Cell cultures aren’t

the perfect re-creation of what’s going on in the human brain,” Hare cautions. But these

types of experiments are “the next best thing for monitoring the chemical changes” in

these neurons, he says.

https://www.sciencenews.org/article/brain-chemical-lost-parkinsons-may-contribute-its-own-demise