Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and l-DOPA-induced dyskinesia

Neurobiol Dis. 2014 Feb;62:307-12. doi: 10.1016/j.nbd.2013.10.016. Epub 2013 Oct 19.

Abstract

A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with l-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission.

Keywords: MPTP; Mass spectrometry; Parkinson's disease; Peptides; Primate; l-DOPA-induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / toxicity*
  • Dyskinesia, Drug-Induced / metabolism*
  • Enkephalins / analysis
  • Enkephalins / metabolism
  • Female
  • Globus Pallidus / chemistry
  • Globus Pallidus / metabolism*
  • Levodopa / toxicity*
  • Macaca mulatta
  • Neuropeptides / analysis
  • Neuropeptides / metabolism*
  • Parkinsonian Disorders / metabolism*
  • Protein Precursors / analysis
  • Protein Precursors / metabolism
  • Putamen / chemistry*
  • Putamen / metabolism
  • Tachykinins / analysis
  • Tachykinins / metabolism

Substances

  • Antiparkinson Agents
  • Enkephalins
  • Neuropeptides
  • Protein Precursors
  • Tachykinins
  • proenkephalin
  • protachykinin
  • Levodopa
  • preproenkephalin