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

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 SOD1G93A 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. © 2018 MRC Laboratory of Molecular Biology.

Citation

Zhen Zhong, Laura Grasso, Caroline Sibilla, Tim J Stevens, Nicholas Barry, Anne Bertolotti. Prion-like protein aggregates exploit the RHO GTPase to cofilin-1 signaling pathway to enter cells. The EMBO journal. 2018 Mar 15;37(6)

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PMID: 29496740

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