Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model
| Autor: | Philip Grant, Susan Skuntz, Sashi Kesavapany, Varsha Shukla, Harish C. Pant, Binukumar Bk, Michaela Prochazkova, Niranjana D. Amin, Ashok B. Kulkarni |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse Neurofilament Hyperphosphorylation Motor nerve Mice Transgenic Nerve Tissue Proteins tau Proteins Biology Neuroprotection Mice 03 medical and health sciences Superoxide Dismutase-1 0302 clinical medicine Genetics medicine Animals Humans Phosphorylation Amyotrophic lateral sclerosis Molecular Biology Genetics (clinical) Motor Neurons Cyclin-dependent kinase 5 Amyotrophic Lateral Sclerosis General Medicine Spinal cord medicine.disease Peptide Fragments Disease Models Animal Phenotype 030104 developmental biology medicine.anatomical_structure nervous system Female General Article Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|