title: Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and l-DOPA-induced dyskinesia.
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.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: Department of Pharmaceutical Biosciences, Biomolecular Imaging and Proteomics, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.affiliation: Department of Pharmaceutical Biosciences, Biomolecular Imaging and Proteomics, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Wadensten
authors.affiliation: Department of Pharmaceutical Biosciences, Biomolecular Imaging and Proteomics, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Fälth
authors.affiliation: Motac Neuroscience, Manchester, UK; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Motac Neuroscience, Manchester, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Crossman
authors.affiliation: Department of Pharmaceutical Biosciences, Biomolecular Imaging and Proteomics, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Motac Neuroscience, Manchester, UK; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China. Electronic address: erwan.bezard@u-bordeaux2.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D004745:Enkephalins / Q000032:analysis / Q000378:metabolism; D005260:Female; D005917:Globus Pallidus / Q000737:chemistry / Q000378:metabolism*; D007980:Levodopa / Q000633:toxicity*; D008253:Macaca mulatta; D009479:Neuropeptides / Q000032:analysis / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000378:metabolism*; D011498:Protein Precursors / Q000032:analysis / Q000378:metabolism; D011699:Putamen / Q000737:chemistry* / Q000378:metabolism; D015320:Tachykinins / Q000032:analysis / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D004745:Enkephalins; D009479:Neuropeptides; D011498:Protein Precursors; D015320:Tachykinins; C029992:proenkephalin; C054618:protachykinin; D007980:Levodopa; C033660:preproenkephalin
keywords: MPTP; Mass spectrometry; Parkinson's disease; Peptides; Primate; l-DOPA-induced dyskinesia