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Browsing by Author "Kuussalo, Lauri"

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  • Kuussalo, Lauri (2024)
    Neurodegenerative disorders are globally the most common cause of disability leading up to 10 million deaths every year, but the mechanisms underlying neurodegeneration are not understood well. Methylation of messenger RNAs (mRNA) at adenosine base position N6 (m6A) by a methyltransferase-complex is a modification that regulates gene expression by influencing mRNA stability, transport, translation and degradation. The mRNA m6A levels are decreased in many neurodegenerative diseases. Our group has shown that dopamine neurons can be rescued, by unknown mechanisms, by activating the methyltransferase-like 3 (Mettl3) enzyme, which increases mRNA m6A levels. The aim of this study was to understand the mechanisms underlying mRNA m6A-induced neuronal survival. We investigated with reverse transcription quantitative polymerase chain reaction (RT-qPCR) how the changes in mRNA m6A modifications affect gene expression. We validated with female rat striatum samples that Mettl3 activation upregulates Neurexophilin-3 (Nxhp3), an important protein for neurotransmitter release and motor functions. Pellino 1 (Peli1), a E3 ubiquiting ligase, was upregulated in nucleus accumbens region of the same rats. Finally, we found with in vitro mouse cortical neurons that Mettl3 inhibition induces endoplasmic reticulum (ER) stress and an unfolded protein response. We saw the activation of inositol-requiring enzyme-1 (Ire1-alpha) and PKR-like ER kinase (Perk) signalling pathways. ER stress is a hallmark of neurodegenerative diseases. This is the first study to show a connection between Mettl3 inhibition and ER stress but the mechanism is still unknow. Further studies need to be performed in order to see if Mettl3 inhibition regulates Ire1-alpha and Perk activity directly, or does Mettl3 inhibition induce ER stress indirectly. Our results highlight how crucial mRNA m6A modification is for neuronal survival.