Parkinson’s disease (PD) is a neurodegenerative disorder which affects more than 10 million people around the world. It is characterised by gradual degeneration and loss of nigrostriatal dopamine (DA) neurons. This results in motor symptoms like rigidity and tremors but also non-motor symptoms like constipation, depression etc. The is no cure for this disease, only alleviation of symptoms is possible. Although experimental administration of neurotrophic factors has shown some promise, they need to be delivered directly into the brain, making the procedure risky and expensive. Importantly, delivery into the brain will not affect non-motor symptoms. Thus, there is a need for drugs that could be delivered systemically and that would cross the blood-brain barrier. Although the aetiology of PD is unknown, certain toxins and mutations are known to contribute. In addition, recent evidence points to a decrease in the methylation of mRNA at adenosine position N6 (m6A). This reversible modification, which is catalysed by methyltransferase like 3 (METTL3), is enriched in neurons and cancer cells affecting the stability, transport and translation of mRNAs.
Our collaborators have developed novel compounds that activate METTL3 and thereby increase cellular m6A levels on mRNA (m6A enhancers). Preliminary testing of these compounds indicated their neuroprotective properties on DA neurons. The main aim of this project was to solidify the importance of mRNA m6A in DA neuron survival. Further, the mechanism of action of how increasing m6A protects neurons was investigated. Finally, the ability of the compounds to penetrate the blood-brain barrier was evaluated. These experiments uncover a completely new pathway for DA neuron protection and pave way for novel therapeutic avenues against PD.
