Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model

被引:23
作者
Binukumar, B. K. [1 ,2 ]
Skuntz, Susan [1 ]
Prochazkova, Michaela [3 ]
Kesavapany, Sashi [4 ]
Amin, Niranjana D. [1 ]
Shukla, Varsha [1 ]
Grant, Philip [1 ]
Kulkarni, Ashok B. [3 ]
Pant, Harish C. [1 ]
机构
[1] NINDS, Neuronal Cytoskeletal Prot Regulat Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA
[2] CSIR, Inst Genom & Integrat Biol, Mathura Rd, New Delhi 110025, India
[3] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, NIH, Bethesda, MD 20892 USA
[4] Nanyang Technol Univ, Natl Inst Hlth Technol, Singapore 637553, Singapore
基金
美国国家卫生研究院;
关键词
CYCLIN-DEPENDENT KINASE-5; GLYCOGEN-SYNTHASE KINASE-3; SUPEROXIDE-DISMUTASE; PROVIDES NEUROPROTECTION; SOD1; MUTATION; TAU-PROTEIN; MPTP MODEL; P35; ACTIVATOR; NEUROFILAMENT;
D O I
10.1093/hmg/ddz118
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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 (SOD1(G37R)). A Cdk5 involvement in motor neuron degeneration is supported by analysis of three SOD1(G37R) 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 SOD1(G37R), 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.
引用
收藏
页码:3175 / 3187
页数:13
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