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

Hum Mol Genet. 2019 Oct 1;28(19):3175-3187. doi: 10.1093/hmg/ddz118.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / cytology*
  • Motor Neurons / metabolism
  • Nerve Tissue Proteins / genetics*
  • Peptide Fragments / genetics*
  • Phenotype
  • Phosphorylation
  • Superoxide Dismutase-1 / genetics
  • tau Proteins / metabolism

Substances

  • Cdk5 inhibitory peptide, human
  • MAPT protein, human
  • Nerve Tissue Proteins
  • Peptide Fragments
  • SOD1 protein, human
  • tau Proteins
  • Superoxide Dismutase-1