Abstract
Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our findings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.
Highlights
Parkin is an E3 ubiquitin-protein ligase with neuroprotective properties
The analysis demonstrated a complete loss of parkin protein in parkin knockout (PKO) rats (Fig. 1A)
Parkin is a neuroprotective ubiquitin protein ligase with multiple substrates and functions, which contributes to development of PD54,55
Summary
Parkin is an E3 ubiquitin-protein ligase with neuroprotective properties. The main function of parkin is associated with the ubiquitin-proteasome system, a predominant cellular pathway responsible for targeting specific proteins for degradation. The studies in PKO mice suggest that loss of parkin protein may result in decreased release of presynaptic DA (reviewed in[8,10]). The major objective of the present study was to characterize the DAergic system in the striatum of young adult (2 month-old) PKO rats in order to characterize compensatory mechanisms that may have occurred in the striatum lacking parkin as well as to elucidate potential early signs of PD in these rats. The activity of MAO-A and the activity of MAO-B were significantly decreased Despite these decreases, there was no indication of the presence of DA-mediated oxidative stress in the striatum of these rats as assessed by lack of an increase in the levels of DA quinones or lipid peroxidation by-product, 2-hydroxynonenal (4-HNE). The locomotor response to methamphetamine was decreased in the knockouts compared to the WT controls
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