Nature paper interpretation! It is revealed that the risk and severity of Parkinson's disease are closely related to ion channel mutations in cell lysosomes

February 4, 2021 // --- Many genetic mutations have been found to be associated with a person's risk of Parkinson's disease.
for most of these mutations, the mechanism of their role is still unclear.
Now, in a new study, researchers from the University of Pennsylvania, Fudan University in China and Peking University have revealed two different mutations--- one that increases the risk of disease and causes people with Parkinson's disease to become more serious, and the other that reduces the risk of disease--- how it develops in the body.
results were published online January 27, 2021 in the journal Nature, under the title "A growth-factor-activated lysosomal K-channel regulations Parkinson's pathology."
photo from Nature, 2021, doi:10.1038/s41586-021-03185-z.
study found that the mutation, which is present in about 17 percent of the body, increases the risk of disease and causes a decrease in the function of an ion channel in a cell called lysosome.
same time, a different mutation that reduced the risk of Parkinson's disease by about 20 percent was present in 7 percent of the general population, enhancing the activity of the same ion channel.
, co-author of the paper and a professor of biology at the University of Pennsylvania's School of Arts and Sciences, said, "We started with basic biology and wanted to understand how ion channels in lysosomes are controlled.
, however, in this study, we found a clear link to Parkinson's disease.
to observe mutations in an ion channel gene that increases or decreases the risk of developing Parkinson's disease is very novel.
" the researchers note that the fact that this ion channel appears to play a vital role in Parkinson's disease also makes it an attractive potential target for developing drugs that slow the progression of the disease.
Scientists have known since the 1930s that cells use carefully regulated ion channels embedded in their mass membranes to control key aspects of their physiological properties, such as shuttles between neurons and electrical impulses from neurons to muscles.
it was not until the past decade that it beed to realize that cells with membranes in their cells, including endosomes and lysosomes, also relied on ion channels for communication.
one of the reasons is that it's hard to see them because the cysts are really small, " says Ren.
past few years, his lab has overcome this technical challenge by studying these membrane ion channels and measuring the ion currents that pass through them.
these ions pass through the ion channel proteins that are turned on and off by specific factors.
about five years ago, Ren's team discovered a membrane protein called TMEM175, which forms an ion channel that allows potassium ions to enter and exit.
same time, other research teams working on genome-wide associations found two mutations in TMEM175 that increased or lowered the risk of Parkinson's disease.
, "One of these mutations is associated with a 20 to 25 percent increased risk of Parkinson's disease in the general population," said Dr. Ren.
if you look only at people who have been diagnosed with Parkinson's disease, the mutation is more frequent.
interested in this connection, Ren found Alice Chen-Plotkin, a physician scientist at the University of Pennsylvania who studies Parkinson's patients.
data from people with Parkinson's disease, Chen-Plotkin and her colleagues found that motor and cognitive impairment progressed faster in patients with one of the mutations in the TMEM175 gene that carried Ren's study.
to find out what this mutation actually does in cells, Ren Labs looked at lysosomes.
isolated, they found that potassium ion currents through TMEM175 are activated by growth factors, proteins such as insulin that respond to the presence of nutrients in the body.
confirmed that TMEM175 appeared to be the only active potassium channel in mouse lysosomes.
when you starv your cells, the protein stops working, " says Ren.
This is exciting for us because it tells us that this is an important mechanism that can be used by this cell to receive communication signals from outside the cell, and perhaps to send communication signals back outside.
"they found that a kinase called AKT, which is usually thought to add a small molecule called a phosphate group to any protein, opens the protein channel with TMEM175.
, however, the AKT turned it on without introducing phosphate groups.
, "The textbook definition of kinase is that it makes protein phosphate.
it's amazing to find out that this kinase works without doing this.
then turned to genetically modified mice carrying the same mutations found in the human population to see how this genetic change affected their ion channel activity.
ion currents in mutant mice with this increased risk of disease were only about 50 percent of those in normal mice, and disappeared without growth factors.
, in contrast, the ion channels of mice carrying this mutation, which reduces the risk of disease, continued to operate for several hours, or even longer than normal mice, without growth factors.
, "It tells you that this mutation somehow helps mice resist the effects of nutrient depletion."
to measure the effects on neurons, they observed that neurons carrying this mutation associated with the more severe Parkinson's disease were more susceptible to toxin and nutrient depletion in cell cultures.
the same is true in human neurons, it means that 17 percent of people carry a mutation that may make their neurons more susceptible to stress," Ren said.
with Kelvin Luk, a researcher at the University of Pennsylvania, who looked at levels of misfolded proteins in neurons cultured in vitro.
in Lewy body ---, a typical feature of Parkinson's disease, these inclusions increased "significantly---" in neurons when the function of TMEM175 decreased.
this is most likely due to impaired function of the lysosome.
and also associated with human Parkinson's disease, mice lacking TMEM175 lost some of the neurotransmitters that produce dopamine, and performed worse on coordinated tests than normal mice.
, along with the findings in humans, the researchers believe their study points to an important factor in Parkinson's disease.
the future, Ren's team hopes to delve deeper into the regulatory mechanism of this ion channel.
their study may reveal not only the molecular damage involved in Parkinson's disease, but also other neurodegenerative diseases ---in particular those associated with lysosomes, including some rare but very serious diseases--- involving molecular damage.
they also wanted to know if the susceptible mutation, which is carried in so many people, could also affect the effects of other genetic mutations on the likelihood of developing Parkinson's disease.
(Bioon.com) Reference: 1. Jinhong Wie et al. A growth-factor-activated lysosomal K+ channel regulates Parkinson's pathology. Nature, 2021, doi:10.1038/s41586-021-03185-z.2.Parkinson's disease risk and severity is tied to a channel in cells' 'recycling centers