Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and L-DOPA-induced dyskinesia Mathieu Bourdenx a,b,1 , Anna Nilsson e,1 , Henrik Wadensten e , Maria Fälth e , Qin Li c,d , Alan R. Crossman c , Per E. Andrén e,2 , Erwan Bezard a,b,c,d, ⁎ ,2 a Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France b CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France c Motac Neuroscience, Manchester, UK d Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China e Department of Pharmaceutical Biosciences, Biomolecular Imaging and Proteomics, Uppsala University, Box 591, SE-75124 Uppsala, Sweden abstract article info Article history: Received 14 September 2013 Revised 7 October 2013 Accepted 10 October 2013 Available online 19 October 2013 Keywords: Parkinson's disease Mass spectrometry Peptides L-DOPA-induced dyskinesia Primate MPTP 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. © 2013 Elsevier Inc. All rights reserved. Introduction L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective treatment for Parkinson's disease (PD) motor symptoms. However, L-DOPA-induced dyskinesia (LID) represents a major complication of treatment for PD. Among several mechanisms, a role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of LID on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity (Aubert et al., 2007; Cenci et al., 1998; Henry et al., 2003; Tel et al., 2002). Parkinsonian and dyskinetic states have been associated with different patterns of expression of precursors of the peptides. Parkinsonism is associated with increased expression of the opioid precursor proenkephalin (PENK) messenger RNA (mRNA) in striatal neurons projecting to the globus pallidus in rodents (globus pallidus externalis (GPe) in primates) and a decreased prodynorphin (PDYN) mRNA expression in striatal neurons projecting to the substantia nigra pars reticulata in rodents and primates and the globus pallidus internalis (GPi) in primates (Aubert et al., 2007; Gerfen et al., 1990; Henry et al., 1999; Morissette et al., 1999; Nisbet et al., 1995; Quik et al., 2002). In the dyskinetic state, expression of PDYN mRNA is increased whereas PENK mRNA is unchanged versus controls, at least when the tissue was taken from animals killed at the peak of dyskinesia severity (Aubert et al., 2007). Few studies have, however, focused on the actual peptides being processed from these precursors. We thus studied, using quantitative mass spectrometry, the peptidergic profiles of the putamen, GPe and GPi in parkinsonian and dyskinetic states using tissue collected from control and 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP)- treated macaque monkeys, acutely or chronically treated with L-DOPA (Fernagut et al., 2010; Porras et al., 2012; Santini et al., 2010). The chronically L-DOPA-treated parkinsonian monkeys were separated into non-dyskinetic and dyskinetic groups. Materials and methods Ethical statement All experiments were carried out in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC) Neurobiology of Disease 62 (2014) 307–312 ⁎ Corresponding author at: Institute of Neurodegenerative Diseases, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux cedex, France. Fax: +33 556986182. E-mail address: erwan.bezard@u-bordeaux2.fr (E. Bezard). Available online on ScienceDirect (www.sciencedirect.com). 1 These authors contributed equally to this work. 2 PEA and EB should be both considered as senior authors with equal contribution. 0969-9961/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nbd.2013.10.016 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi