Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc). In vitro, a contribution to neuroinflammation and neurotoxicity has been shown for the lysosomal protease cathepsin X; however, its expression and its role in PD remain unknown. Therefore, the current study was designed to address the regional, cellular, and subcellular localization and activity of cathepsin X in hemi-parkinsonian rats with 6-hydroxydopamine (6-OHDA)-induced excitotoxicity in the unilateral medial forebrain bundle (MFB) lesion. We report for the first time that cathepsin X expression and activity are rapidly increased in the ipsilateral SNc after injection of 6-OHDA into the MFB reaching a maximum after 12 h but seem to stay strongly upregulated after 4 weeks after injection. At early time points of 6-OHDA injection into the MFB, the increased cathepsin X is localized in the lysosomes in the neuronal, predominantly tyrosine hydroxylase-positive dopaminergic cells. After 12 h of 6-OHDA induced lesion, only a few activated microglial cells are positive for cathepsin X whereas, in 4 weeks post-lesion accompanied with complete loss of dopaminergic neurons, there is persistent cathepsin X upregulation restricted to activated glia cells. Taken together, our results demonstrate that cathepsin X upregulation in the lesioned dopaminergic system may play a role as a pathogenic factor in PD. Moreover, inhibition of cathepsin X expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in the PD.
Highlights
Parkinson’s disease is an age-related neurodegenerative disease with a primary pathology characterized by a progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) (Qin et al, 2007)
In order to elucidate the expression of cathepsin X during the 6-OHDA-induced lesion in vivo, male rats were unilaterally lesioned by an injection of 6-OHDA into the right medial forebrain bundle (MFB)
The staining intensities of TH-positive fibers in the striatum were similar in contralateral and ipsilateral sides, even at 48 h 6-OHDA injection (Supplementary Figure S1A). These results indicate that the early time points of injection of 6-OHDAinduced neurodegeneration leads to rapid loss of TH-positive neurons in SNc; the intensity of the TH immunosignal in the striatum was not changed from 12 to 48 h after 6-OHDA injection
Summary
Parkinson’s disease is an age-related neurodegenerative disease with a primary pathology characterized by a progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) (Qin et al, 2007). Microglia – the resident immune cells of the central nervous system (CNS) – are involved in a plethora of neurodegenerative pathologies and, interestingly, show a higher density in the SNc and striatum than in other brain areas (Prinz and Priller, 2014; Haas et al, 2016). In addition to inflammatory cytokines, activated microglia secrete cathepsins, which may promote neurodegeneration and contribute to neuronal loss in PD (Pislar and Kos, 2014)
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