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Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

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Mutations in ion channels contribute to neurological disorders, but determining the basis of their role in pathophysiology is often unclear. In humans, 2 mutations have been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2 bp frameshift mutation (F139WfsX24) and TRESK-C110R, a missense mutation. Despite the fact that both mutants strongly inhibit TRESK, only TRESK-MT leads to an increase in sensory neuron excitability and is associated with a migraine phenotype. Here, we identify a new mechanism, termed frameshift mutation induced Alternative Translation Initiation (fsATI) that may explain why TRESK-MT but not TRESK-C110R is associated with migraine disorder. fsATI leads, from the same TRESK-MT mRNA, to two proteins: TRESK-MT1 and TRESK-MT2. We show that by co-assembling with and inhibiting TREK1 and TREK2, another subfamily of K2P channels, overexpression of TRESK-MT2 increases trigeminal sensory neuron excitability, a key component of migraine induction, leading to a migraine-like phenotype. This finding identifies TREK as a potential molecular target in migraine pathophysiology and resolves the contradictory lack of effect of TRESK-C110R which targets only TRESK and not TREK. Finally, taking into account the potential for fsATI allowed us to identify a new migraine-related TRESK mutant, Y121LfsX44, which also leads to the production of two TRESK fragments, indicating that this mechanism may be widespread. Together, our results suggest that genetic analysis of disease-related mutations should consider fsATI as a distinct class of mutations.

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Articles publicats en revistes (Biomedicina)

# metadata.dc.title[].value
Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK