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Published on: October 13, 2018
Identifying ROCK2 as an intervention target for bilirubin encephalopathy
Bingbing Ke1, Linfei Mao1, Mu Hu2
1Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Bilirubin encephalopathy causes brain damage. This study identifies Rho-associated protein kinase 2 (ROCK2) as a key player, showing ROCK2 inhibition protects against neuronal damage and improves hearing and cognition in models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Neonatal bilirubin encephalopathy causes auditory and cognitive deficits.
- Molecular mechanisms of bilirubin neurotoxicity are not fully understood, limiting therapeutic development.
Purpose of the Study:
- Identify molecular targets for treating bilirubin encephalopathy.
- Investigate the role of Rho-associated protein kinase 2 (ROCK2) in bilirubin-induced neurotoxicity.
Main Methods:
- Quantitative phosphoproteomics and kinase activity prediction identified ROCK2.
- Molecular docking and MicroScale Thermophoresis assessed bilirubin-ROCK2 binding.
- In vitro and in vivo studies used ROCK2 inhibitors and Rock2+/- mice.
- Neuronal and behavioral assessments evaluated therapeutic effects.
Main Results:
- Bilirubin exposure increased ROCK2 protein expression and stability.
- Bilirubin exposure elevated phosphorylation of ROCK2 substrate LIMK1.
- ROCK2 inhibition protected neurons from bilirubin-induced damage.
- ROCK2 modulation improved auditory and cognitive deficits in animal models.
Conclusions:
- ROCK2 is a critical mediator of bilirubin neurotoxicity.
- ROCK2 represents a promising therapeutic target for bilirubin encephalopathy.
- Targeting ROCK2 may restore synaptic function and prevent neuronal damage.
