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Neuronal necrosis is regulated by a conserved chromatin-modifying cascade

Kai Liu1, Lianggong Ding1, Yuhong Li2

  • 1The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;

Proceedings of the National Academy of Sciences of the United States of America
|September 10, 2014
PubMed

Insights

Neuronal necrosis, a cause of brain dysfunction, is regulated by a newly discovered chromatin-modifying cascade involving JIL-1 kinase. This finding offers potential therapeutic targets for stroke and brain trauma.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neuronal necrosis, triggered by calcium overload, leads to severe brain dysfunction in conditions like stroke and trauma.
  • This process was previously thought to be stochastic, lacking genetic regulation, with no effective pharmacological treatments available.

Purpose of the Study:

  • To identify genetic regulators of neuronal necrosis.
  • To investigate the potential of targeting these regulators for therapeutic interventions in brain injury.

Main Methods:

  • Utilized a Drosophila model of calcium overload to identify key regulatory proteins.
  • Investigated the role of JIL-1/mitogen- and stress-activated protein kinase 1/2 (MSK1/2) in neuronal necrosis.
  • Examined downstream events including histone H3 serine 28 phosphorylation (H3S28ph), polycomb repressive complex 1 (PRC1), and Trithorax (Trx).
  • Validated findings in rat cortical neuron cultures and rodent models of brain ischemia.

Main Results:

  • Identified JIL-1/MSK1/2 as a crucial regulator of neuronal necrosis via H3S28ph.
  • Demonstrated that JIL-1 regulates necrosis by displacing PRC1 and activating Trx.
  • Confirmed the activation of the JIL-1/PRC1/Trx cascade in mammalian models of neuronal injury.
  • Showed that inhibiting this cascade reduces neuronal necrosis both in vitro and in vivo.

Conclusions:

  • Neuronal necrosis is controlled by a specific chromatin-modifying cascade.
  • The JIL-1/PRC1/Trx pathway represents a novel therapeutic target for mitigating neuronal death in brain diseases.
  • This cascade may also serve as a potential biomarker for neuronal necrosis.
Keywords:
H3K4me3agingepigeneticshistone modificationneurodegeneration

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