Parkinson's disease (PD), a prevalent neurodegenerative disorder, lacks therapies to halt progression. L-ergothioneine (EGT), a fungal-derived compound with blood-brain barrier permeability and neuroprotective traits (lower in PD patients), was studied. In MPTP-induced PD mice, EGT improved motor dysfunction, with high doses matching Rasagiline's efficacy. Mechanistically, EGT acts via DJ-1: activating DJ-1-Nrf2 to reduce oxidative stress and preserve dopaminergic neurons, and DJ-1-Nurr1 to restore dopamine levels by upregulating key enzymes, easing motor issues. EGT holds potential as a PD drug or lead compound.
A research team from the University of Science and Technology of China has applied EGT to PD research, confirming its preventive and therapeutic effects at both cellular and animal levels. They preliminarily explored its mechanism of action and proposed that EGT could serve as a potential drug or lead compound for anti-PD drug development.
DOI: 10.26599/FSHW.2024.9250068
EGT Alleviates MPTP-Induced Motor Dysfunction in PD Model Mice
The exogenous neurotoxin MPTP selectively damages the nigrostriatal DA pathway, inducing a PD mouse model. The authors established a subacute PD model by administering MPTP (30 mg/kg/day) for seven consecutive days. Rasagiline, a clinical PD treatment, was used as a positive control. To investigate EGT's effects on MPTP-induced motor dysfunction, behavioral tests, including the open field test and rotarod test, were conducted.
Graphical Abstract
The open field test evaluates spontaneous locomotor activity. Compared to the control group, MPTP-treated mice exhibited significantly reduced total movement distance and average speed (Figures 1C and D). However, these deficits were ameliorated by EGT treatment, with the high-dose EGT group (EGT-H) showing effects comparable to Rasagiline (Figures 1C and D). The time spent in the center reflects exploratory behavior and anxiety levels. MPTP-treated mice entered the center less frequently, but EGT treatment restored this behavior (Figures 1B and E).
Additionally, motor coordination was assessed using the rotarod test. MPTP-treated mice showed significantly shorter latency to fall than the control group, whereas EGT-treated mice exhibited improved motor coordination.
Mechanism Exploration: How EGT Improves PD Pathology
DJ-1 has been extensively studied for its roles in signal transduction and transcriptional regulation. Clements et al. demonstrated that DJ-1 promotes the dissociation of Nrf2 from Keap1 and facilitates Nrf2 nuclear translocation. Lu et al. found that DJ-1 enhances Nurr1 transcriptional activity, increasing the expression of tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), and vesicular monoamine transporter 2 (VMAT2). Therefore, the authors investigated whether EGT's neuroprotective effects depend on DJ-1.
Figure 1 shows that in the MPTP-induced Parkinson's disease mouse model, after treatment with different doses of ergothioneine (EGT), the mice's total movement distance, average speed, and number of entries into the central area in the open field test, as well as the fall latency in the rotarod test were improved, and the effect of high-dose EGT was similar to that of rasagiline.
Immunofluorescence in the SN revealed that EGT significantly reversed MPTP-induced DJ-1 suppression (Figures 8A and B). In MN9D cells, EGT most strongly activated DJ-1 at 40 μmol/L or after 18 hours of treatment (Figures 8C-E). Notably, DJ-1 knockdown (si-DJ-1) markedly reduced EGT-induced DJ-1 protein expression (Figures 8F and G). Furthermore, si-DJ-1 blocked EGT-enhanced nuclear translocation of Nrf2 and Nurr1 (Figures 8F-I).
EGT's ability to restore MPP⁺-downregulated SOD1 and SOD2 mRNA levels was also abolished by si-DJ-1. Additionally, DJ-1 silencing diminished EGT's capacity to reduce MPP⁺-induced ROS accumulation and apoptosis (Figures 8J-N), indicating that EGT relies on DJ-1 to mitigate oxidative stress-induced neuronal death. Similarly, si-DJ-1 prevented EGT from upregulating TH and DDC mRNA levels (Figures 8O and P) and attenuated EGT's restoration of MPP⁺-reduced DA levels (Figure 8Q).
Conclusion
In summary, the authors found that ergothioneine restores DA levels by activating the DJ-1-Nurr1 pathway, thereby alleviating motor dysfunction. Additionally, EGT suppresses oxidative stress by activating the DJ-1-Nrf2 pathway, rescuing DAergic neuron loss. These findings suggest that EGT may serve as a potential therapeutic agent for PD or a lead compound for anti-PD drug development.