Upregulation of Cysteine Protease Cathepsin X in the 6-Hydroxydopamine Model of Parkinson’s Disease

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.

Therapeutic potential of inhibition of the neuroinflammation induced cathepsin X:in vivoevidence

“…These results are in agreement with our recent in vivo study using a hemi-parkinsonian 6-OHDA rat model of PD. Four weeks post-lesion, we observed a persistent cathepsin X upregulation restricted to glial cells concentrated in the ipsilateral SNc (Pislar et al, 2018). The data obtained in the present study are in line also with other reports showing glial upregulation of certain cysteine cathepsins in LPS-induced neuroinflammation (Fan et al, 2015;Fan et al, 2012).…”

“…We recently showed the upregulation of cathepsin X in degenerated rat brain using a 6-OHDA rat PD experimental model. Unilateral 6-OHDA-induced lesion of the nigrostriatal pathways rapidly increased cathepsin X expression and activity in the ipsilateral SNc, which was mainly localized in TH-positive dopaminergic neurons, whereas a late time point of 6-OHDA-induced lesion caused persistent cathepsin X upregulation restricted to activated glia cells (Pislar et al, 2018). Thus, cathepsin X could be involved in neuroinflammation-induced dopaminergic neurodegeneration.…”

“…Additionally, cathepsin X also promotes the apoptosis of neuronal cells induced by the neurotoxin 6-hydroxydopamine (6-OHDA), which was reversed with cathepsin X downregulation or inhibition by the specific cathepsin X inhibitor . Moreover, in vivo cathepsin X expression and its activity have been found to be strongly increased in the SNc of hemi-parkinsonian rats with 6-OHDA-induced excitotoxicity in the unilateral medial forebrain bundle, indicating that cathepsin X may be involved in the pathogenic cascade event in PD (Pislar et al, 2018). In addition to a role in neurodegeneration, the involvement of cathepsin X in inflammation-induced neurodegeneration has been reported.…”

Neuroinflammation-Induced Upregulation of Glial Cathepsin X Expression and Activity in vivo

“…Unilateral 6-OHDA-induced lesion of the nigrostriatal pathways rapidly increased cathepsin X expression and activity in the ipsilateral SNc, which was mainly localized in TH-positive dopaminergic neurons. The effect was observed at 12 h of 6-OHDA injection, whereas a late time point of 6-OHDAinduced lesion, namely 4 weeks, caused persistent cathepsin X upregulation restricted to activated glia cells (Pislar et al, 2018). Thus, cathepsin X could be involved in neuroinflammationinduced dopaminergic neurodegeneration.…”

“…Additionally, cathepsin X also promotes the apoptosis of neuronal cells induced by the neurotoxin 6-hydroxydopamine (6-OHDA), which was reversed with cathepsin X downregulation or inhibition by the specific cathepsin X inhibitor . Moreover, ex vivo cathepsin X expression and its activity have been found to be strongly increased in the SNc of hemi-parkinsonian rats with 6-OHDA-induced excitotoxicity in the unilateral medial forebrain bundle, indicating that cathepsin X may be involved in the pathogenic cascade event in PD (Pislar et al, 2018). In addition to a role in neurodegeneration, the involvement of cathepsin X in inflammation-induced neurodegeneration has been reported.…”