Ricerc@Sapienza

The RNA-binding protein FUS participates in several RNA biosynthetic processes and has
been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA
(circRNA) production. We identified circRNAs expressed in
in vitro
-derived mouse motor
neurons (MNs) and determined that the production of a considerable number of these
circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-asso-
ciated FUS mutants, we directly correlate the modulation of circRNA biogenesis with
alteration of FUS nuclear levels and with putative toxic gain of function activities. We also
demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the
back-splicing junctions and that this control can be reproduced with artificial constructs. Most
circRNAs are conserved in humans and specific ones are deregulated in human-induced
pluripotent stem cell-derived MNs carrying the FUS
P525L
mutation associated with ALS