A new study in Pennsylvania found that genetic differences associated with increases and reductions in the risk of developing neurodegenerative disease alter the functioning of ion channels within cellular organelles called lysosomes.
Several gene mutations have been found to be linked to a person’s risk of developing Parkinson’s disease. However, for most of these variables, the mechanism by which they operate remains unclear.
Now a new study is on nature A team from the University of Pennsylvania revealed how two different differences appear in the body – one that increases the risk of disease and leads to more severe disease in people who develop Parkinson’s disease and the other reduces the risk.
The work, led by Dejian Ren, a professor in the Department of Biology at the College of Arts and Sciences, showed that a variation that increases the risk of disease, which about 17% of people have, causes a decrease in the function of the ion channel in cells. Organelles called lysosomes, also known as cell waste removal and recycling centers. Meanwhile, a different variation that reduces the risk of developing Parkinson’s disease by about 20% and is found in 7% of the general population enhances the activity of the same ion channel.
“We started with basic biology, and we want to understand how these lysosomal ducts are controlled,” says Raine. But here we found this clear link with Parkinson’s disease. Knowing that you can get variation in the ion channel gene that can change the odds of developing Parkinson’s disease in both directions – increase and decrease it – is very new. “
The researchers noted that the fact that the duct appears to play a crucial role in Parkinson’s disease also makes it an attractive potential target for a drug that could slow the disease’s progression.
Scientists since the 1930s have understood that cells use carefully structured ion channels embedded in the plasma membrane to control critical aspects of physiology, such as the transmission of electrical impulses between neurons and from neurons to muscles.
But it wasn’t until the past decade that researchers began to estimate that intracellular membrane-containing organelles, including endosomes and lysosomes, also depend on ion channels for communication.
“One of the reasons is that it’s difficult to look at it because the organelles are so small,” says Raine. Over the past several years, his lab overcame this technical challenge and began to study membrane channels and measure the stream of ions that passed through them.
These ions pass through channel proteins that open and close in response to specific factors. About five years ago, Rennes’ group identified a single membrane protein, TMEM175, that forms a channel that allows potassium ions to move in and out.
Around the same time, other teams doing genome-wide association studies have found two variants in TMEM175 affect the risk of developing Parkinson’s disease, raising or lowering it.
“One difference is linked to a 20-25% increase in the odds of developing Parkinson’s disease in the general population,” says Raine. “And if you only look at people diagnosed with Parkinson’s disease, the frequency of that difference is higher.”
Intrigued by the connection, Rain reached out to Pennsylvania physician and scientist Alice Chen Plotkin, who works with patients with Parkinson’s disease, to collaborate. In data from Parkinson’s patients, she and her colleagues found that movement and cognitive disabilities develop more rapidly in patients who carry one of the TMEM175 genetic variants that Rennes was studying.
To see what this difference was actually doing in cells, Rennes’ lab focused on lysosomes. In isolation, they found that the potassium stream through TMEM175 is activated by growth factors, and proteins such as insulin that respond to the presence of nutrients in the body. They confirmed that TMEM175 appears to be the only active potassium conduit in rat lysosomes.
“When a cell gets hungry, that protein doesn’t work anymore,” says Raine. “This was exciting to us because that tells us that this is a key mechanism that the organelle can use to receive communication from outside the cell and possibly send the connection back.”
They found that a kinase enzyme called AKT, which is usually thought to accomplish its ends by adding a small molecule called a phosphate group to whatever protein it acts on, joins TMEM175 to open the protein channel. But AKT opened it without introducing a phosphate group. “The textbook definition of kinase is that it phosphorylates proteins,” says Raine. “Finding this kinase to act without doing it was very surprising.”
They then turned to the mice that were genetically modified to carry the same differences that were found in humans to see how the genetic changes affect ion channel activity in animals. Mice with a mutation that increased the risk of developing the disease had a potassium current of only about 50% that of normal mice, and this current was quenched in the absence of growth factors. In contrast, the ion channels in the mutation-infected mice continued to reduce the risk of disease at work for several hours in the absence of growth factors, even for a longer period than in the normal mice.
“This tells you that this mutation somehow helps mice withstand the effects of nutrient depletion,” Ren says.
To measure the effects on neurons, they observed that neurons with the mutation in cell culture associated with more severe Parkinson’s disease were more prone to damage from toxins and nutrient depletion. “If the same was true of human neurons, then that means that 17% of the population carries a variety that may make their neurons more damaged when they are under stress,” says Raine.
In collaboration with University of Pennsylvania researcher Kelvin Locke, the researchers looked at levels of an abnormal protein in neurons in cell culture. Rinne, known in humans as Lewy bodies and a characteristic of Parkinson’s disease, says these “amazing” inclusions within neurons were increased when TMEM175 function decreased. This is likely due to a poor function of lysosomes, which normally aid in cell waste recycling and recycling.
It has also been associated with human Parkinson’s disease – mice lacking TMEM175 lost a portion of the neurons that produce the neurotransmitter dopamine and performed worse on coordination tests compared to normal mice.
Combined with the results in humans, the researchers believe their work points to a significant contributor to Parkinson’s disease pathology. From now on, Rennes’ group hopes to delve into the mechanism by which this ion channel is regulated. Their research may shed light not only on molecular disorders associated with Parkinson’s disease but also in other neurodegenerative diseases, especially those related to particulate matter, which includes a number of rare but very serious conditions.
They also want to know if this predisposing difference held by many people, it also affects how other gene mutations contribute to someone’s likelihood of developing Parkinson’s disease.
Digian Ren is Professor of Biology in the University of Pennsylvania College of Arts and Sciences.
Rin’s co-authors are Jinhong Wie, Zhenjiang Liu, Chunlei Cang, Kimberly Aranda, and Joey Lohmann of Penn College of Arts and Sciences. Tropea, Willing Liang, and Alice S. Chen Plotkin, and Kelvin C. Locke of Perelman Medical College in Pence; Haikun Song and Boxon Lu from Fudan University of China; Lu Yang, Huanhuan Wang and Jing Yang from Peking University of China. Jinhong Wie is the first author and Ren, Chen-Plotkin and Luk are the opposite authors.
The work was partially supported by the National Institutes of Health (grants GM133172, HL147379, NS088322, NS115139, NS053488, and AG062418).
Katherine Unger Bailey
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