Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 19, Pages 3175-3187Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz118
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Funding
- Intramural Research Programs of the National Institutes of Health
- National Institute of Neurological Disorders, USA
- National Institute of Dental and Craniofacial Research, USA
- Council of Scientific & Industrial Research (CSIR), India
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000664] Funding Source: NIH RePORTER
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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.
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