Methylmercury (MeHg), a potent environmental neurotoxicant, induces selective neuronal cell death primarily in the cerebellum and cerebral cortex. Its ability to cross the blood-brain barrier and accumulate in neural tissues leads to severe neurological impairments, as seen in Minamata disease. Despite extensive research, the precise molecular mechanisms linking MeHg exposure to neuronal loss remain incompletely understood. Emerging evidence suggests that endoplasmic reticulum (ER) stress and oxidative stress are central to MeHg-induced neurotoxicity. However, how these stress pathways transition from adaptive responses to pro-apoptotic signals is still unclear.
To investigate this, we employed ERAI transgenic mice, which express a luciferase reporter under the control of the XBP1 promoter—a key component of the unfolded protein response (UPR). This system allows real-time monitoring of ER stress activation in vivo. Upon subcutaneous administration of MeHg (25 mg/kg), bioluminescence imaging revealed significant activation of the UPR in multiple organs, with the most pronounced signal observed in the liver, followed by moderate increases in the brain, heart, and kidneys. These findings confirm that MeHg induces systemic ER stress, particularly in highly perfused tissues.
Further analysis using ERAI-Venus mice enabled detailed spatiotemporal mapping of ER stress at the cellular level. Time-course experiments showed a transient increase in XBP1DBD-Venus fluorescence in the somatosensory cortex, peaking after three weeks of exposure via drinking water (30 ppm MeHg-GSH complex). The signal gradually declined thereafter, suggesting an initial protective UPR response that was eventually overwhelmed. Notably, the auditory and visual cortices exhibited stronger early signals than the motor cortex, indicating region-specific sensitivity to MeHg-induced ER stress.MAS825 supplier
Immunohistochemical analysis revealed that nearly all ERAI-positive cells co-localized with NeuN, a neuronal nuclear marker, confirming that neurons are the primary responders to MeHg-triggered ER stress.210302-17-3 Molecular Weight In contrast, minimal co-expression was observed in GFAP-positive astrocytes or Iba1-positive microglia, although weak signals in microglia were likely due to phagocytosis of dying neurons.PMID:34915069 This highlights the neuron-specific vulnerability to MeHg toxicity.
At the molecular level, the cytoprotective IRE1-XBP1 axis was initially activated, evidenced by upregulation of HRD1—an ERAD-related E3 ubiquitin ligase—peaking at week 3. However, prolonged exposure led to a decline in XBP1 mRNA splicing, likely due to S-mercuration of IRE1 by MeHg. Concurrently, the pro-apoptotic PERK-ATF6 branches became increasingly active, with CHOP expression rising progressively over time. Colocalization of CHOP with NeuN confirmed that neurons initiate apoptosis via ER stress.
These results demonstrate a biphasic UPR response: an early adaptive phase involving chaperone induction and protein quality control, followed by a switch to apoptosis driven by sustained MeHg accumulation. This transition explains the delayed onset of neuronal death despite early ER stress detection. Our findings suggest that therapeutic strategies aimed at stabilizing the IRE1-XBP1 axis or inhibiting CHOP activation may mitigate MeHg-induced neuropathy. The ERAI mouse model provides a powerful tool for dissecting site- and cell-specific neurotoxicity and offers new insights into the temporal regulation of UPR signaling in neurodegeneration.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com