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

• Published in: PloS one 2019-08, Vol.14 (8), p.e0220056
• Main Authors: Choi, Brian K A, D'Onofrio, Philippe M, Shabanzadeh, Alireza P, Koeberle, Paulo D
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry; Biology and Life Sciences; Cancer; Cell Cycle; Cell death; Cell division; Cell survival; Central nervous system; Central Nervous System - drug effects; Central Nervous System - injuries; Central Nervous System - pathology; Cilia; Cilia - drug effects; Cilia - physiology; Cycles; Disease; Dismantling; Etoposide - pharmacology; Female; Hypoxia; Injuries; Injury prevention; Kinases; Medicine and Health Sciences; Nervous system diseases; Neurodegenerative diseases; Neurological diseases; Neurons; Neurons - drug effects; Neurons - pathology; Neuroprotection; Optic nerve; Optic Nerve Injuries - drug therapy; Optic Nerve Injuries - pathology; Organelles; Phosphorylation; Protective Agents - pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Rehabilitation; Retina; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - pathology; Retinoblastoma; Stabilization; Surgery; Transcription factors; Traumatic brain injury
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220056

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.