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Aberrant activation of CDK5 is involved in the pathogenesis of OPIDN

Ying-Peng Wang1, Dan-Lei Mou, Jun-Feng Song

  • 1Institute of Neurosciences, The Fourth Military Medical University, Xi'an, China.

Journal of Neurochemistry
|September 22, 2006
PubMed

Insights

Organophosphate-induced delayed neuropathy (OPIDN) is linked to triorthocresyl phosphate (TOCP) exposure. Aberrant activation of cyclin-dependent kinase 5 (CDK5) and its activator p35/p25 in the spinal cord appears to play a role in OPIDN development.

Area of Science:

  • Neuroscience
  • Toxicology
  • Biochemistry

Background:

  • Triorthocresyl phosphate (TOCP) exposure can cause organophosphate-induced delayed neuropathy (OPIDN).
  • Cyclin-dependent kinase 5 (CDK5) and its activators (p35/p25) are crucial for neuronal function.
  • Dysregulation of CDK5 has been implicated in various neurological disorders.

Purpose of the Study:

  • To investigate the role of CDK5 and its activator p35/p25 in the pathogenesis of OPIDN.
  • To examine the temporal changes in CDK5, p35, and p25 expression and localization in the spinal cord following TOCP exposure.
  • To assess the effect of a CDK5 inhibitor on axonal transport in TOCP-treated hens.

Main Methods:

  • Adult hens were administered a single dose of TOCP and examined at multiple time points (3-18 days post-exposure).
  • Immunohistochemistry and Western blotting were used to evaluate CDK5, p35/p25 expression, phosphorylation, and localization in the lumbar spinal cord.
  • Roscovitine, a CDK5 inhibitor, was administered to a subset of hens to assess its impact on axonal transport.

Main Results:

  • Hens exhibited clinical signs of OPIDN around day 9 post-TOCP exposure.
  • A significant increase in phosphorylated CDK5 (p-CDK5) and p35-positive cells was observed, along with co-localization and mislocalization of p-CDK5 and p35/p25 in neurons.
  • Protein levels of CDK5, p-CDK5, p35, and p25, as well as the p25/p35 ratio, increased, peaking around day 9.
  • Roscovitine treatment improved axonal transport in TOCP-exposed nerves compared to controls.

Conclusions:

  • Aberrant activation and altered localization of CDK5 and its activator p35/p25 are associated with the development of OPIDN.
  • These findings suggest that dysregulation of the CDK5 pathway is a key factor in the pathogenesis of organophosphate-induced delayed neuropathy.
  • Targeting CDK5 activity may offer a potential therapeutic strategy for OPIDN.

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