The risk and severity of Parkinson’s disease is associated with channels in cell recycling centers

Many genetic mutations have been shown to be associated with the risk of developing Parkinson’s disease. However, for most of these variants, the mechanism by which they act remains unclear.

Now new research Nature A team led by a team at the University of Pennsylvania has shown how two different variations increase. Illness risk It causes more serious illness in people who develop Parkinson’s disease or in others who reduce their risk. This appears in the body.

The study, led by Dejian Ren, a professor of biology in the Faculty of Arts and Sciences, change Increases the risk of illness that about 17% of people have and reduces the function of ions channel An organelle called a lysosome, also known as a cell waste removal and recycling center.Meanwhile, another variation present in 7%, reducing the risk of Parkinson’s disease by about 20%. General population Strengthen the activity of the same ion channel.

“We started with the basic biology of wanting to understand how these lysosomal channels are regulated,” says Len. “But here we have discovered this clear relationship with Parkinson’s disease. Being able to have changes in ion channel genes that can alter the probability of developing both ways of increasing and decreasing Parkinson’s disease. It’s very novel to see. “

The fact that channels appear to play an important role in Parkinson’s disease also makes it an attractive potential target for drugs that can slow the progression of the disease, researchers point out. There is.

Scientists have understood that cells have used carefully regulated ion channels since the 1930s. Protoplasmic membrane It controls important aspects of physiology, such as the round trip of electrical impulses between neurons and from neurons to muscles.

However, it was only in the last decade that researchers began to recognize that intracellular organelles with membranes such as endosomes and lysosomes also depend on ion channels to communicate.

“One reason is that the organelles are so small that it’s hard to see them,” says Len. Over the past few years, his lab has overcome this technical challenge and has begun studying these membrane channels and measuring the current of ions passing through them.

These ions pass through channel proteins that open and close in response to specific factors. About five years ago, Ren’s group identified one membrane protein, TMEM175, that forms channels that allow potassium ions to enter and exit.

At about the same time, other teams Genome-wide association study We discovered two variations of TMEM175 that affect the risk of Parkinson’s disease and raised or lowered it.

“One variation is associated with a 20-25% increase in the probability of developing Parkinson’s disease in the general population,” says Len. “And if you look only at those who have been diagnosed with Parkinson’s disease, the frequency of fluctuations is even higher.”

Intrigued by this connection, Len contacted Alice Chen Protokin, a medical scientist at the University of Pennsylvania, who works with patients with Parkinson’s disease. In data from patients with Parkinson’s disease, she and her colleagues found that movement and cognitive deficits progressed more rapidly in patients with one of the TMEM175 genetic mutations that Len was studying.

To find out what this change actually does in cells, Len’s lab turned to lysosomes. Alone, they found that the potassium current through TMEM175 was activated by growth factors, proteins like insulin that respond to the presence of nutrients in the body. And they confirmed that TMEM175 appears to be the only active potassium channel in mouse lysosomes.

“When you starve cells, this protein stops working,” says Len. “It was exciting for us because it shows that organelles are the primary mechanism that can be used to receive and possibly send back communications from outside the cell.”

They found that a kinase enzyme called AKT would achieve that goal by adding a small molecule called a phosphate group to the protein in action, binding to TMEM175 to open protein channels. Did. However, AKT opened it without introducing a phosphate group. “The definition in kinase textbooks is that it phosphorylates proteins,” says Len. “It was very surprising to find this kinase working without it.”

They then turned to mice that were genetically engineered to carry the same variations found in. population Find out how genetic changes affected ion channel activity in animals. Mice with mutations that increased the risk of disease accounted for approximately 50% of the potassium current in normal mice, and that current disappeared in the absence of growth factors. In contrast, the ion channels of mice with disease risk-reducing mutations continued to operate for several hours in the absence of growth factors, even longer than in normal mice.

“This tells you that this mutation somehow helps mice resist the effects of nutrient depletion,” says Len.

To measure their effects on neurons, they observed that neurons with cell culture mutations associated with more severe Parkinson’s disease were susceptible to damage from toxin and nutrient depletion. “If the same applies to human neurons, it means that 17% of the population has mutations that can cause more damage to neurons when exposed to stressors,” Ren says. ..

In collaboration with Penn researcher Kelvin Luck, the researchers examined the levels of misfolded proteins in cells in cell culture. Known in humans as Lewy bodies, these inclusion bodies, which are characteristic of Parkinson’s disease, increased “significantly” in neurons when TMEM175 function declined, Ren said. This may be due to impaired lysosomal function. Lysosomes usually help digest and recycle waste products produced by cells.

Also, in relation to human Parkinson’s disease, mice lacking TMEM175 lost some of the neurons that produce the neurotransmitter dopamine, resulting in poorer performance in coordination tests than normal mice.

Researchers believe that, along with human discoveries, their work represents an important contributor to the pathology of Parkinson’s disease.In the future, Ren’s group hopes to dig deeper into the mechanism through this. Ion channel It is regulated. Their research may shed light on other neurodegenerative diseases, especially those associated with lysosomes, as well as molecular disorders associated with Parkinson’s disease. This includes a number of rare but very serious conditions.

They also want to know if this predisposing mutation is carried by so many people that it also affects other methods. Genetic mutation Contributes to the likelihood that someone will develop Parkinson’s disease.