PT  - JOURNAL ARTICLE
AU  - Fanny Eysert
AU  - Audrey Coulon
AU  - Emmanuelle Boscher
AU  - Anaїs-Camille Vreulx
AU  - Amandine Flaig
AU  - Tiago Mendes
AU  - Sandrine Hughes
AU  - Benjamin Grenier-Boley
AU  - Xavier Hanoulle
AU  - Florie Demiautte
AU  - Charlotte Bauer
AU  - Mikael Marttinen
AU  - Mari Takalo
AU  - Philippe Amouyel
AU  - Shruti Desai
AU  - Ian Pike
AU  - Mikko Hiltunen
AU  - Frédéric Chécler
AU  - Mélissa Farinelli
AU  - Charlotte Delay
AU  - Nicolas Malmanche
AU  - Sébastien Hébert
AU  - Julie Dumont
AU  - Devrim Kilinc
AU  - Jean-Charles Lambert
AU  - Julien Chapuis
TI  - Alzheimer’s genetic risk factor <em>FERMT2</em> (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner
AID  - 10.1101/767194
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 767194
4099  - http://biorxiv.org/content/early/2020/07/17/767194.short
4100  - http://biorxiv.org/content/early/2020/07/17/767194.full
AB  - 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 Alzheimer’s 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 3’UTR 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.Competing Interest StatementS. H. and M. F. are full-time employees of E-Phy-Science SA. C. D. has been an employee of Janssen Pharmaceutica since her departure from the laboratory Inserm U1167 in 2016.