TMEM230 gene shown to cause Parkinson’s disease

Scientists have discovered a new cause of Parkinson’s disease – mutations in a gene called TMEM230.

This appears to be the third gene definitively linked to confirmed cases of the common movement disorder.

In a study, Northwestern University scientists provide evidence of TMEM230 mutations in patients with Parkinson’s disease from both North America and Asia. They also demonstrated that the gene is responsible for producing a protein involved in packaging the neurotransmitter dopamine in neurons. Loss of dopamine-producing neurons is a defining characteristic of Parkinson’s disease.

The study’s findings provide new clues to explain how Parkinson’s disease develops in the brain. Those clues may inform future therapies for the disorder.

Commenting on the research, principal investigator Dr Teepu Siddique said: “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.”

About 15 percent of Parkinson’s disease cases are thought to be caused by genetics, primarily by mutations in two genes called SNCA and LRRK2. Siddique said that other genes have only been associated with features of parkinsonism, a general term for neurological disorders with motor symptoms.

20 years of research

The Northwestern Medicine team’s proof that mutations in TMEM230 lead to Parkinson’s disease is the result of 20 years of research conducted with collaborators around the world.

The project began in 1996, when Siddique and Dr Han-Xiang Deng began investigating a family with 15 members who had typical symptoms of Parkinson’s disease. Using DNA samples provided by Dr Ali Rajput, from the University of Saskatchewan, Siddique and Deng performed genome-wide analysis on 65 of the family’s members, including 13 with the disease, in hopes of finding a common mutation that could explain the prevalence.

They were able to narrow the search down to a small region of DNA on chromosome 20 that contained 141 known genes. Using whole exome sequencing technology, they then compared DNA variations in one healthy family member to those in four family members with the disease. The scientists found more than 90,000 variants before eventually identifying TMEM230 as the gene with disease-causing mutation.

Synaptic vesicles

The scientists discovered that 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 one cell to another.

“Current symptomatic treatments for Parkinson’s disease increase the neurotransmitter dopamine that is released by these synaptic vesicles to cells that project into different parts of the brain controlling motor activity, mood and many other organ systems affected by the disease,” Siddique said.

The scientists hypothesise that the protein is involved in the movement of these vesicles.

“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,” Deng said. “Our new findings suggest that normalising synaptic vesicle trafficking may be a strategy for future therapeutic development. We can develop drugs to promote this critical pathway.”

In future research, Siddique and Deng plan to explore how TMEM230 mutations cause disease using mouse models.