Stabilization of primary cilia reduces abortive cell cycle re-entry to protect injured adult CNS neurons from apoptosis

PloS One
Brian K A ChoiPaulo D Koeberle

Abstract

Abortive cell cycle (ACC) re-entry of apoptotic neurons is a recently characterized phenomenon that occurs after central nervous system (CNS) injury or over the course of CNS disease. Consequently, inhibiting cell cycle progression is neuroprotective in numerous CNS pathology models. Primary cilia are ubiquitous, centriole-based cellular organelles that prevent cell cycling, but their ability to modulate abortive cell cycle has not been described. Here, we show that neuronal cilia are ablated in-vitro and in-vivo following injury by hypoxia or optic nerve transection (ONT), respectively. Furthermore, forced cilia resorption sensitized neurons to these injuries and enhanced cell death. In contrast, pharmacological inhibition or shRNA knockdown of the proteins that disassemble the cilia increased neuron survival and decreased the phosphorylation of retinoblastoma (Rb), a master switch for cell cycle re-entry. Our findings show that the stabilization of neuronal primary cilia inhibits, at least transiently, apoptotic cell cycling, which has implications for future therapeutic strategies that halt or slow the progression of neurodegenerative diseases and acute CNS injuries.

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Citations

Apr 1, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xinhua LiShuying Yang
Dec 8, 2020·Frontiers in Cell and Developmental Biology·Mayu HosioEsko Kankuri
Feb 20, 2021·Scientific Reports·Junguee LeeMinho Shong
Feb 26, 2021·Proceedings of the National Academy of Sciences of the United States of America·Lili XieLarry Benowitz

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Methods Mentioned

BETA
sedation
dissection
confocal microscopy

Software Mentioned

Imaris
GraphPad
GraphPad InStat
Zen

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

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