Related Experiment Video
Updated: May 8, 2026
In vivo Imaging of Optic Nerve Fiber Integrity by Contrast-Enhanced MRI in Mice
Published on: July 22, 2014
Endoplasmic reticulum stress signaling involvement in manganese-induced nerve cell damage in organotypic brain slice
1Department of Environmental Health, School of Public Health, China Medical University, People's Republic of China.
Abstract:
Overexposure to manganese (Mn) has been known to induce neuronal damage. However, the mechanisms underlying the neurotoxicity of Mn are still incompletely understood but seem to involve endoplasmic reticulum (ER) stress. The current study investigated whether ER stress signaling was involved in Mn-induced neurotoxicity in organotypic brain slices. After the brain slices were respectively exposed to 400μM Mn for 0, 6, 12, 18, 24h, there was a time-dependent increase in apoptotic cell death in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, Mn was found to upregulate GRP78/94, CHOP and caspase-12 expression. Furthermore, PERK phosphorylation, PERK-mediated phosphorylation of eIF2a and ATF4 mRNA expression increased. IRE1 activation and Xbp1 mRNA splicing also increased. However, ATF6 p90 levels did not change. The findings clearly demonstrated that Mn induced the ER stress via activation of PERK and IRE1 signaling pathway, which contributed to the occurrence of apoptosis in cultured slices.
Insights
Manganese (Mn) exposure causes brain cell death by triggering endoplasmic reticulum (ER) stress. This study shows Mn activates specific ER stress pathways, leading to apoptosis in brain slices.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) overexposure is linked to neuronal damage.
- Mechanisms of Mn neurotoxicity are not fully understood but may involve endoplasmic reticulum (ER) stress.
Purpose of the Study:
- To investigate the role of ER stress signaling in Mn-induced neurotoxicity.
- To examine Mn's effects on organotypic brain slices.
Main Methods:
- Organotypic brain slices were exposed to 400μM Mn for varying durations (0-24h).
- Apoptotic cell death and lactate dehydrogenase (LDH) release were measured.
- Expression of ER stress markers (GRP78/94, CHOP, caspase-12), PERK pathway components (PERK, eIF2a, ATF4), and IRE1 pathway components (IRE1, Xbp1) were analyzed.
Main Results:
- Mn exposure led to a time-dependent increase in apoptotic cell death and LDH release.
- Mn upregulated GRP78/94, CHOP, and caspase-12 expression.
- Activation of the PERK pathway (PERK phosphorylation, eIF2a phosphorylation, ATF4 expression) and IRE1 pathway (IRE1 activation, Xbp1 splicing) was observed.
- ATF6 pathway activation was not detected.
Conclusions:
- Mn induces ER stress in brain slices through the activation of PERK and IRE1 signaling pathways.
- This ER stress contributes to Mn-induced apoptosis in cultured brain slices.
