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Monday, June 6, 2016

What Causes Parkinson’s Disease?

After 20 Years Of Research, Scientists Find Third Gene Linked To Neurodegenerative Disease 

Jun 6, 2016 03:12 PM By Lecia Bushak


Researchers at Northwestern University toiled for two decades to uncover a third gene linked to Parkinson’s disease, and now they’ve finally identified it as TMEM230. In a new study published in Nature Genetics, the research team shows how a mutation in the gene that creates a dopamine-related protein leads to the disease.
Parkinson’s is a heterogeneous disease, meaning most cases are caused by a variation of genetic factors. There are many genetic factors that have been shown to play a role in possibly prompting the disease, but there are only two other confirmed genes that, when carrying mutations, lead to Parkinson’s disease directly — SNCA and LRRK2. Fifteen percent of Parkinson’s disease cases are caused by genetics, and SNCA and LRRK2 are thought to make up the majority of that percentage. And while scientists have pinpointed other things that contribute to the disease — including environmental factors, loss of dopamine, age, and gender — most are just associations and not direct causes.
“Previous research has associated Parkinson’s disease with various factors in the environment, but the only direct causes that are known are genetic,” said Dr. Teepu Siddique, a professor at Northwestern and lead author of the study, in a statement. “Many genes have been claimed to cause Parkinson’s disease, but they haven’t been validated. We show that mutations in this new gene lead to pathologically and clinically proven cases of the disease.”
Typical Parkinson's symptoms include hand tremors and movement problems, though it has been difficult to pinpoint a single cause for the neurodegenerative disease. Pixabay, public domain

A FAMILY’S COMMON GENE MUTATION

In 1996, Siddique and fellow researcher Dr. Han-Xiang Deng began studying a family in which 15 members had Parkinson’s disease symptoms. Those symptoms typically involve hand tremors, slow movements, stiffness, difficulty walking, and loss of balance. The researchers used DNA samples to complete genome-wide analyses on the whole family, including healthy members (65 people total), as well as 13 who had been diagnosed with Parkinson’s. They hoped to find one common gene mutation that could explain why so many members of the family had the disease.
Finally, after years of searching, the researchers pinpointed a small region of DNA on chromosome 20. They sorted through some 141 known genes involved in the area, as well as 90,000 DNA variations in comparisons of healthy and Parkinson’s-diagnosed family members. It turned out that TMEM230 was the gene in question, a novel gene that had never been discovered before.
“This was a totally new gene,” Deng said in the statement. “We didn’t know its function. So we did a series of studies to find out where the protein encoded by this gene is located and what it does.”
TMEM230’s job is to encode a protein that plays a role in the synaptic vesicles of neurons, which store neurotransmitters like dopamine before they’re released from cell to cell in a process called vesicle trafficking. Parkinson’s has been associated with low dopamine levels in the past, and the researchers believe that the TMEM230 mutation impairs dopamine production.
“We believe that vesicle trafficking defects are a key mechanism of Parkinson’s disease, not just for cases with this mutation, but a common pathway for the majority of cases,” said Deng in the statement. “All three of the authenticated genes are concentrated on synaptic vesicles. Our new findings suggest that normalizing synaptic vesicle trafficking may be a strategy for future therapeutic development. We can develop drugs to promote this critical pathway.”
The researchers also found that beyond the original family studied, TMEM230 mutations were present in other families throughout North America and even Asia. “This particular gene causing Parkinson’s disease is not just limited to one population in North America,” said Siddique in the statement. “It’s worldwide, found in very different ethnic and environmental conditions. These mutations are that strong.”
In the future, Siddique and his team plan on further exploring how TMEM230 mutations work and create disease by examining how they play out in mouse models.
Source: Siddique T, Deng H, Rajput A, et al. Nature Genetics , 2016.
http://www.medicaldaily.com/parkinsons-disease-human-brain-genetics-dopamine-neurotransmitter-388788?

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