Northwestern Medicine researchers 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 published in Nature Genetics, the researchers have provided 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.
Taken together, 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, which currently has no cure and few known causes.
Previous research has associated Parkinson's disease with various factors in the environment, but the only direct causes that are known are genetic.
About 15% of Parkinson's disease cases are thought to be caused by genetics, primarily by mutations in two genes called SNCA and LRRK2.
Other genes have only been associated with features of parkinsonism, a general term for neurological disorders with motor symptoms.
The Northwestern Medicine team's proof that mutations in TMEM230 lead to Parkinson's disease is the result of 20 years of research.
The project began in 1996, when researchers began investigating a family with 15 members who had typical symptoms of Parkinson's disease. Using DNA samples they 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 investigators found more than 90,000 variants before eventually identifying TMEM230 as the gene with disease-causing mutation.
TMEM230 encodes a protein that extends across the membrane of tiny sacks inside neurons called synaptic vesicles, which store neurotransmitters before they're 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.
The investigators hypothesize that the protein is involved in the movement of these vesicles. 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. Normalizing synaptic vesicle trafficking may be a strategy for future therapeutic development.
The research team also found mutations in the TMEM230 gene in cases of Parkinson's disease in additional families in North America and as far away as China. They verified that these patients had both clinical characteristics of the disease ( symptoms like tremors, slow movement and stiffness ) as well as pathological evidence in the brain ( loss of dopamine neurons and abnormal accumulations of proteins inside surviving neurons ). ( Xagena )
Source: Northwestern University, 2016