Mutations in a gene involved in vesicle trafficking, called TMEM230, can result in Parkinson's disease
In the latest study published in Nature Genetics, TMEM230 has been identified as the 3rd gene definitively linked to Parkinson's disease. The gene is involved in the packing and trafficking of neurotransmitters, which perhaps isn't a surprise considering Parkinson's is characterised by a dysfunctional dopamine system and dopamine neuron loss.
"Previous research has associated Parkinson's disease with various factors in the environment, but the only direct causes that are known are genetic. 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"
What other genes are linked to Parkinson's?
Around 15% of Parkinson's cases are believed to be genetically caused, and 2 genes in particular, SNCA and LRRK2 have been linked to the disease so far. SNCA mutations alter the expression of a protein called alpha-synuclein which is present in the lew body clumps seen in Parkinson's, and LRRK2 encodes for a protein called dardarin. LRRK2 plays a role in oxidative stress, mitochondrial dysfunction, autophagy (cellular recycling) and inflammation. There are a range of additional associated genes too, but they are linked to a minority of cases of the disease.
How was TMEM230 identified?
In a study lasting 20 years, researchers analysed a family with 15 members afflicted by Parkinson's. After conducting genomic analysis on 65 of the family members, they compared more than 90,000 variations before arriving at the culprit - TMEM230.
"This was a totally new gene. We didn't know its function. So we did a series of studies to find out where the protein encoded by this gene is located and what it does"
Further work revealed that TMEM230 produces a protein present on the membrane of synaptic vesicles, which package and store neurotransmitters. Curiously, all 3 genes are closely involved with synaptic vesicles and vesicle trafficking, and Parkinson's is defined by impaired dopamine production. The researchers believe that synaptic vesicle trafficking could therefore be a new therapeutic area for drug development.
A wider picture
Surprisingly (or perhaps not so surprisingly), the team discovered TMEM230 mutations in additional families in both China and North America. Again, patients with the mutations were displaying symptoms including tremors and stiffness, as well as the characteristic loss of dopamine neurons and formation of Lewy bodies.
"This particular gene causing Parkinson's disease is not just limited to one population in North America. It's worldwide, found in very different ethnic and environmental conditions. These mutations are that strong"
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