The effect of striatal pre-enkephalin overexpression in the basal ganglia of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

• Published in: The European journal of neuroscience 2014-07, Vol.40 (2), p.2406-2416
• Main Authors: Bissonnette, Stéphanie, Muratot, Sophie, Vernoux, Nathalie, Bezeau, François, Calon, Frédéric, Hébert, Sébastien S., Samadi, Pershia
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dopamine; Dopamine - metabolism; Enkephalins - genetics; Enkephalins - metabolism; globus pallidus; Globus Pallidus - metabolism; Locomotion; Male; Medical sciences; Mice; Mice, Inbred C57BL; MPTP Poisoning - metabolism; MPTP Poisoning - physiopathology; Nervous system (semeiology, syndromes); Nervous system as a whole; neurodegeneration; Neurology; opioid; Protein Precursors - genetics; Protein Precursors - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; striatum; Substantia Nigra - metabolism; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12596

The midbrain dopamine (DA) cell death underlying Parkinson's disease (PD) is associated with upregulation of pre‐enkephalin (pENK) in striatopallidal neurons. Our previous results obtained with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) parkinsonian monkeys suggest that increased striatal expression of pENK mRNA is a compensatory mechanism to alleviate PD‐related motor symptoms. In this study, we tested the hypothesis that increased pENK expression in the striatum protects against the neurotoxic insults of MPTP in mice. To this end, recombinant adeno‐associated virus serotype 2 also containing green fluorescent protein was used to overexpress pENK prior to DA depletion. Our results showed that overexpression of pENK in the striatum of MPTP mice induced: (i) increased levels of the opioid peptide enkephalin (ENK) in the striatum; (ii) higher densities of ENK‐positive fibers in both the globus pallidus (GP) and the substantia nigra; (iii) higher locomotor activity; and (iv) a higher density of striatal tyrosine hydroxylase‐positive fibers in the striatum. In addition, striatal overexpression of pENK in MPTP ‐treated mice led to 52 and 43% higher DA concentrations and DA turnover, respectively, in the GP compared to sham‐treated MPTP mice. These observations are in agreement with the idea that increased expression of pENK at an early stage of disease can improve PD symptoms. We provide evidence that in MPTP mouse model of Parkinson's disease, viral vector‐mediated striatal overexpression of pENK before dopamine depletion reduced degeneration of nigrostriatal dopaminergic terminals, and increased dopamine concentration and dopamine turnover in the globus pallidus. Therefore, increased expression of ENK in the basal ganglia could have protective effects against MPTP insult.