Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

Abstract Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin‐1 to remodel cortical actin and enter cells. Upstream of cofilin‐1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin‐1 activity to remodel actin and modulate aggregate entry. In the spinal cord of symptomatic SOD1 G93A transgenic mice, cofilin‐1 phosphorylation is increased and actin dynamics altered. Importantly, the RHO to cofilin‐1 signalling pathway also modulates entry of tau and α‐synuclein aggregates. Our results identify a common host cell signalling pathway that diverse protein aggregates exploit to remodel actin and enter cells.