New Genetic Cause Found in Familial Parkinson’s Disease

A recent publication in the journal Nature Genetics describes a new genetic cause of Parkinson’s disease.

The newly identified gene, called TMEM230, is involved in storage and release of the neurotransmitter dopamine from neurons. The findings open up new avenues of research into mechanisms leading to the disease, for which no cure exists.

“Previous research has associated Parkinson’s disease with various factors in the environment, but the only direct causes that are known are genetic,” study leader Dr. Teepu Siddique, a 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.”

The road to the discovery of TMEM230 as a causative Parkinson’s gene has not been brief. Starting 20 years ago, Dr. Siddique and the study’s first author Dr. Han-Xiang Deng, investigated a family where 15 related individuals were affected by Parkinson’s symptoms.

Working through a genome-wide association study involving 65 family members, including three who were affected by disease, allowed them to narrow down their search to a particular region on chromosome 20.

This region holds 141 genes, so the team started the rigorous process of sequencing the genes’ coding regions, comparing DNA base pairs between sick and healthy family members. The meticulous search generated 90,000 variants that the scientists went through before arriving at TMEM230 as the cause of Parkinson’s disease in the family.

The finding brought them more work. TMEM230 had never been examined before, and no one knew what function it played in the body.

“So we did a series of studies to find out where the protein, encoded by this gene, is located and what it does,” Deng said.

Further work, summarized in the report “Identification of TMEM230 mutations in familial Parkinson’s disease,” revealed that the protein encoded by the gene is an integral part of synaptic vesicles, tiny sacs storing neurotransmitters within neurons, releasing them upon arrival of nerve impulses.

The research team believes that the protein somehow regulates vesicles’ movement.

“We believe that vesicle trafficking defects are a key mechanism of Parkinson’s disease, not just for cases with this mutation, but is a common pathway for the majority of cases,” 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.”

Dr. Siddique and his team did not settle with identifying the gene in one family.

Equipped with the new knowledge, they sought other families affected by Parkinson’s who carried mutations in TMEM230. The found North American and Asian families with Parkinson’s symptoms and brain changes typical of Parkinson’s –  such as the death of dopaminergic neurons and the presence of protein inclusions in remaining nerve cells.

“This particular gene causing Parkinson’s disease is not just limited to one population in North America,” said Siddique. “It’s worldwide, found in very different ethnic and environmental conditions. These mutations are that strong.”

The research team now plans to use mice to study how mutations in TMEM230 cause disease.