Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) is regulated by risk allele-binding of miR-4504 and leads to synaptic dysfunction in an APP-dependent manner

Eysert, F.; Coulon, A.; Boscher, E.; Vreulx, A.-C.; Flaig, A.; Mendes, T.; Hughes, S.; Grenier-Boley, B.; Hanoulle, X.; Demiautte, F.; Marttinen, M.; Takalo, M.; Amouyel, P.; Desai, S.; Pike, I.; Hiltunen, M.; Farinelli, M.; Delay, C.; Malmanche, N.; Hebert, S.; Dumont, J.; Kilinc, D.; Lambert, J.-C.; Chapuis, J.

doi:10.1101/767194

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bioRxiv · 10.1101/767194

Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) is regulated by risk allele-binding of miR-4504 and leads to synaptic dysfunction in an APP-dependent manner

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Abstract

Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimers disease (AD), as a potential key modulator of axon guidance; a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.

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Eysert, F., Coulon, A., Boscher, E., Vreulx, A.-C., Flaig, A., Mendes, T., Hughes, S., Grenier-Boley, B., Hanoulle, X., Demiautte, F., Marttinen, M., Takalo, M., Amouyel, P., Desai, S., Pike, I., Hiltunen, M., Farinelli, M., Delay, C., Malmanche, N., Hebert, S., Dumont, J., Kilinc, D., Lambert, J.-C., Chapuis, J.. 2019-09-13. Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) is regulated by risk allele-binding of miR-4504 and leads to synaptic dysfunction in an APP-dependent manner. https://doi.org/10.1101/767194

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