Northwestern scientists single out new mutation linked to Parkinson’s disease

Neuron

Parkinson’s disease is a neurodegenerative disorder that impacts motor function and progressively causes dementia, especially in older patients. Research has shown that 15% of Parkinson's cases are caused by a mutation in one of two genes. Now researchers have uncovered a third mutation in a new gene. The results may guide towards better diagnosis and point towards future drug targets for Parkinson's.

The research was led by Teepu Siddique of Northwestern University, and his team published its findings in the journal Nature Genetics.

The causative mechanism for Parkinson's isn’t fully understood, and scientists have pulled out many genes that might be responsible for causing the neurodegenerative disease. Of these, mutations in either SNCA and/or LRRK2 genes appear strikingly common between patients with Parkinson's, and these mutations are thought to be present in 15% of all cases.

"Previous research has associated Parkinson's disease with various factors in the environment, but the only direct causes that are known are genetic," said Siddique in a 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."

In a study that spanned over 20 years, Siddique and colleagues performed exome sequencing on 65 people from the same family with a high prevalence of Parkinson's. This whole genome approach allowed them to identify important expressed genes among the family--of which 13 members were identified as having Parkinson's. On chromosome 20 they picked up a gene called TMEM230 to have a disease-causing mutation.

"This was a totally new gene. We didn't know its function," first author Han-Xiang Deng explained 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."

Pursuing the gene's function they found it codes for a protein that is involved in the membrane of synaptic vesicles--the vehicles for transporting neurotransmitters between neurons. A neurotransmitter called dopamine is responsible for the deteriorating symptoms of Parkinson's, and the TMEM230 protein may be important for the normal trafficking of dopamine.

"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 in the release. "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."

They found the mutation to be common in Parkinson's worldwide by screening additional families in North America as well as families in China. Their next plan is to create a Parkinson's mouse model with the TMEM230 mutation and study the progression of the disease.

- here’s the abstract
- here’s the release

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