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

Brian K A Choi,Philippe M D’Onofrio,Alireza P Shabanzadeh,Paulo D Koeberle,Rafael Linden

doi:10.1371/journal.pone.0220056

Brian K A Choi, Philippe M D’Onofrio + Show 3 more

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https://doi.org/10.1371/journal.pone.0220056

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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.

Highlights

Fatal cell cycle re-entry by neurons, known as abortive cell cycling (ACC), has been observed in a number of central nervous system (CNS) diseases such as Alzheimer’s and Parkinson’s disease [1,2] or insults that include stroke [3] and traumatic brain injury (TBI) [4]
Sublethal hypoxic stress induces ciliary shortening that is reversed by normoxia To investigate if ACC can be modulated by primary cilia, we sought to establish whether apoptotic stimuli alters cilia expression in neurons
Cultures that were returned to normoxic conditions after hypoxia demonstrated a re-expression of primary cilia that were shorter in length compared to pre-hypoxic cells (Fig 1A, Right)

Summary

Introduction

Fatal cell cycle re-entry by neurons, known as abortive cell cycling (ACC), has been observed in a number of CNS diseases such as Alzheimer’s and Parkinson’s disease [1,2] or insults that include stroke [3] and traumatic brain injury (TBI) [4]. Inhibiting cell cycle progression, through cyclin dependent kinase (CDK) inhibitors or knockout of mitotic transcription factors, has been neuroprotective in a number of CNS injury models, implicating ACC as a critical process in neuronal apoptosis [5,6,7,8]. Primary cilia are solitary projections of the cell body that suppress cell cycle by sequestering centrioles at the cell membrane [9,10].

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