肌萎缩侧索硬化
生物
细胞周期蛋白依赖激酶5
运动神经元
神经保护
神经科学
高磷酸化
转基因小鼠
脊髓
神经丝
转基因
细胞生物学
激酶
免疫学
疾病
病理
蛋白激酶A
医学
遗传学
基因
细胞周期蛋白依赖激酶2
免疫组织化学
作者
B. Binukumar,Susan Skuntz,Michaela Prochazkova,Sashi Kesavapany,Niranjana D. Amin,Varsha Shukla,Philip Grant,Ashok B. Kulkarni,Harish C. Pant
摘要
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor nerve cells in the brain and the spinal cord. Etiological mechanisms underlying the disease remain poorly understood; recent studies suggest that deregulation of p25/Cyclin-dependent kinase 5 (Cdk5) activity leads to the hyperphosphorylation of Tau and neurofilament (NF) proteins in ALS transgenic mouse model (SOD1G37R). A Cdk5 involvement in motor neuron degeneration is supported by analysis of three SOD1G37R mouse lines exhibiting perikaryal inclusions of NF proteins and hyperphosphorylation of Tau. Here, we tested the hypothesis that inhibition of Cdk5/p25 hyperactivation in vivo is a neuroprotective factor during ALS pathogenesis by crossing the new transgenic mouse line that overexpresses Cdk5 inhibitory peptide (CIP) in motor neurons with the SOD1G37R, ALS mouse model (TriTg mouse line). The overexpression of CIP in the motor neurons significantly improves motor deficits, extends survival and delays pathology in brain and spinal cord of TriTg mice. In addition, overexpression of CIP in motor neurons significantly delays neuroinflammatory responses in TriTg mouse. Taken together, these data suggest that CIP may serve as a novel therapeutic agent for the treatment of neurodegenerative diseases.
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