Wlds-mediated protection of dopaminergic fibers in an animal model of Parkinson disease

Parkinson disease (PD) is characterized by the progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Since the deficit in striatal dopamine is the main cause of PD symptoms, it appears critical to preserve axon terminals [1]. Significant axon protection from peripheral nerve Wallerian degeneration is observed in W/d(s) mice [2-5], a phenotype conferred by a spontaneous dominant mutation [6]. To assess any W/d(s)-mediated rescue of dopamine fibers in a PD model, the nigrostriatal pathway of W/d(s), mice was lesioned with 6-hydroxydopamine (6-OHDA), a catecholaminergic neurotoxin [7]. Following 6-OHDA injection in the medial forebrain bundle, W/d(s) mice showed remarkable dopamine fiber protection in the striatum. Drug-induced rotational behavior confirmed the nigrostriatal fiber ability to release dopamine, although revealing an abnormal neurotransmitter control presumably due to disrupted axonal transport. Following 6-OHDA injection in the midstriatum, only a protection trend was observed. Strikingly, no protection of W/d(s) nigral dopaminergic cell bodies was obtained following either nigrostriatal lesion. Besides showing subtle differences in the degeneration process between subcellular compartments, the reported W/d(s)-mediated protection of the dopamine axon terminals in an animal model of PD may lead to the understanding of mechanisms underlying axon loss and to the development of new therapeutic approaches.