The Third Gene Linked To Parkinson’s Found
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. This is a discovery that comes following the death of legendary boxer Muhammad Ali, who suffered from the neurodegenerative disease for three decades.
Mutations were discovered in a gene identified as TMEM230. Scientists provided evidence of the TMEM230 mutations in the study, which is published in Nature Genetics. They found TMEM230 produced a protein involved in the packaging of dopamine in neurons, which is significant because Parkinson’s is marked by the breakdown of dopamine-producing neurons.
Parkinson’s disease is a nervous disorder and 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,” Dr. Teepu Siddique, principal investigator in the study and professor at Northwestern University Feinberg School of Medicine, said in a news release.
“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,” he added.
Study authors analyzed the genes of 65 family members— 13 with the disease and 52 without— to look for commonalities among those with Parkinson’s. They narrowed in on a DNA region on chromosome 20 that contained 141 known genes and used whole exome sequencing to identify more than 90,000 genetic variants. Among those variants was TMEM230, which appeared to be the disease-causing mutation.
“This was a totally new gene. We didn’t know its function,” study co-author Dr. Han-Xiang Deng, a neurology professor at Northwestern, said in the release. “So we did a series of studies to find out where the protein encoded by this gene is located and what it does.”
According to the scientists, TMEM230 encodes a protein that extends across the membrane of tiny sacks inside neurons called synaptic vesicles, which store neurotransmitters before they are released from cell to cell in a process known as vesicle trafficking.
Parkinson’s has been associated with low dopamine levels in previous studies, and the scientists believe that the TMEM230 mutation damages 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. All three of the authenticated genes are concentrated on synaptic vesicles,” said Deng.
“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,” he added.
The scientists also discovered mutations in the TMEM230 gene in other Parkinson’s disease cases in families in North America and in China. 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.
