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

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

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

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Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
© 2018 EMBO
ISSN
0261-4189
eISSN
1460-2075
D.O.I.
10.15252/embj.201797822
Publisher site
See Article on Publisher Site

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 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.

Journal

The EMBO JournalWiley

Published: Jan 15, 2018

Keywords: ; ; ; ;

References

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