Prosaposin PS18 reduces dopaminergic neurodegeneration in a 6-hydroxydopamine rat model of Parkinson's disease

by Selleckchem | Jul 03 2023

Saposin and its precursor prosaposin are endogenous proteins with neurotrophic and anti-apoptotic properties. Prosaposin or its analog prosaposin-derived 18-mer peptide (PS18) reduced neuronal damage in hippocampus and apoptosis in stroke brain. Its role in Parkinson's disease (PD) has not been well characterized. This study aimed to examine the physiological role of PS18 in 6-hydroxydopamine (6-OHDA) cellular and animal models of PD. We found that PS18 significantly antagonized 6-OHDA -mediated dopaminergic neuronal loss and TUNEL in rat primary dopaminergic neuronal culture. In SH-SY5Y cells overexpressing the secreted ER calcium-monitoring proteins, we found that PS18 significantly reduced thapsigargin and 6-OHDA-mediated ER stress. The expression of prosaposin and the protective effect of PS18 were next examined in hemiparkinsonian rats. 6-OHDA was unilaterally administered to striatum. The expression of prosaposin was transiently upregulated in striatum on D3 (day 3) after lesioning and returned below the basal level on D29. The 6-OHDA-lesioned rats developed bradykinesia and an increase in methamphetamine-mediated rotation, which was antagonized by PS18. Brain tissues were collected for Western blot, immunohistochemistry, and qRTPCR analysis. Tyrosine hydroxylase immunoreactivity was significantly reduced while the expressions of PERK, ATF6, CHOP, and BiP were upregulated in the lesioned nigra; these responses were significantly antagonized by PS18. Taken together, our data support that PS18 is neuroprotective in cellular and animal models of PD. The mechanisms of protection may involve anti-ER stress.

Comments:

The study you described aimed to investigate the physiological role of a peptide called prosaposin-derived 18-mer peptide (PS18) in cellular and animal models of Parkinson's disease (PD). The researchers focused on the effects of PS18 on dopaminergic neuronal loss and apoptosis in PD-related models.

In rat primary dopaminergic neuronal cultures treated with 6-hydroxydopamine (6-OHDA), a neurotoxin commonly used to induce PD-like symptoms in experimental models, PS18 was found to significantly counteract the 6-OHDA-induced loss of dopaminergic neurons and reduce apoptosis, as measured by the TUNEL assay. This suggests that PS18 has a protective effect on dopaminergic neurons in this cellular model of PD.

The researchers also examined the effects of PS18 on endoplasmic reticulum (ER) stress, which is known to be involved in PD pathology. They used SH-SY5Y cells overexpressing secreted ER calcium-monitoring proteins and found that PS18 reduced ER stress induced by both thapsigargin and 6-OHDA. This indicates that PS18 has the ability to alleviate ER stress in PD-related cellular models.

In an animal model of PD, hemiparkinsonian rats were created by administering 6-OHDA unilaterally into the striatum, a brain region affected in PD. The expression of prosaposin, the precursor of PS18, was transiently upregulated in the striatum on day 3 after the lesion, but returned to basal levels by day 29. The rats that received the 6-OHDA lesion exhibited bradykinesia (slowness of movement) and an increase in methamphetamine-induced rotation, both of which are characteristic motor symptoms of PD. However, treatment with PS18 was able to antagonize these motor deficits, suggesting a beneficial effect of PS18 in this animal model.

Further analysis of brain tissues from the lesioned nigra, another brain region affected in PD, revealed that the immunoreactivity of tyrosine hydroxylase, an enzyme involved in dopamine synthesis, was significantly reduced. In addition, the expressions of several ER stress markers, including PERK, ATF6, CHOP, and BiP, were upregulated in the lesioned nigra. However, treatment with PS18 significantly counteracted these changes, indicating its potential to mitigate ER stress and protect dopaminergic neurons in the nigra.

In summary, the findings of this study suggest that PS18 has neuroprotective effects in cellular and animal models of PD. Its mechanisms of action may involve reducing dopaminergic neuronal loss, inhibiting apoptosis, and alleviating ER stress, which are all implicated in the pathogenesis of PD. These results highlight the potential therapeutic role of PS18 in the treatment of PD, although further research is needed to fully understand its effectiveness and potential clinical applications.