Modulation of Unfolded Protein Response by Methylmercury

Hiraoka, Hideki; Nakahara, Kengo; Kaneko, Yuki; Akiyama, Shiori; Okuda, Kosaku; Fujimura, Masatake; Kumagai, Yoshito; Takasugi, Nobumasa; Uehara, Takashi

doi:10.1248/bpb.b17-00359

Cited by 13 publications

(16 citation statements)

References 20 publications

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“…However, the presence of both toxins suggests a synergistic or, at minimum, additive potential to induce neurodegeneration. Possible mechanisms of combined toxicity may include both BMAA’s and MeHg’s ability to cause glutathione depletion, glutamate dyshomeostasis, mitochondrial dysfunction, and the stimulation of the unfolded protein response [ 15 , 44 , 68 , 69 , 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

Garamszegi

Banack

et al. 2021

Toxins

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Dolphins are well-regarded sentinels for toxin exposure and can bioaccumulate a cyanotoxin called β-N-methylamino-l-alanine (BMAA) that has been linked to human neurodegenerative disease. The same dolphins also possessed hallmarks of Alzheimer’s disease (AD), suggesting a possible association between toxin exposure and neuropathology. However, the mechanisms of neurodegeneration in dolphins and the impact cyanotoxins have on these processes are unknown. Here, we evaluate BMAA exposure by investigating transcription signatures using PCR for dolphin genes homologous to those implicated in AD and related dementias: APP, PSEN1, PSEN2, MAPT, GRN, TARDBP, and C9orf72. Immunohistochemistry and Sevier Münger silver staining were used to validate neuropathology. Methylmercury (MeHg), a synergistic neurotoxicant with BMAA, was also measured using PT-GC-AFS. We report that dolphins have up to a three-fold increase in gene transcription related to Aβ+ plaques, neurofibrillary tangles, neuritic plaques, and TDP-43+ intracytoplasmic inclusions. The upregulation of gene transcription in our dolphin cohort paralleled increasing BMAA concentration. In addition, dolphins with BMAA exposures equivalent to those reported in AD patients displayed up to a 14-fold increase in AD-type neuropathology. MeHg was detected (0.16–0.41 μg/g) and toxicity associated with exposure was also observed in the brain. These results demonstrate that dolphins develop neuropathology associated with AD and exposure to BMAA and MeHg may augment these processes.

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Section: Discussionmentioning

confidence: 99%

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

Garamszegi

Banack

et al. 2021

Toxins

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“…MeHg is thought to trigger apoptosis via induction of ER stress caused by caspase activation [114,116]. Additionally, we found that S -mercuration of IRE1α interferes IRE1α–XBP1 signaling (Figure 1 [119]). Activation of IRE1α–TRAF2–ASK1 pathway was also observed in XBP1-deficient cells [120].…”

Section: Mehg and Er Stressmentioning

confidence: 87%

The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

Takasugi

Hiraoka

Nakahara

et al. 2019

IJMS

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The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.

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“…S4a). In a previous study, we showed that high-dose MeHg blocked XBP1 mRNA splicing in vitro (Hiraoka et al 2017). Thus, we hypothesized that in the late phase of MeHg exposure, the ERAI signal is decreased due to the decline in XBP1 mRNA splicing.…”

Section: Activation Of Upr Branches By Mehg Exposurementioning

confidence: 91%

“…Next, we focused on the transient upregulation of ERAI signaling by MeHg in the somatosensory cortex. We previously showed that XBP1 mRNA splicing is attenuated by exposure to high-dose MeHg, suggesting that IRE1α is a target of S-mercuration (Hiraoka et al 2017). Thus, a decrease in the ERAI signal indicates a decline in XBP1 mRNA splicing or degradation of the ERAI molecule.…”

Section: Activation Of Upr Branches By Mehg Exposurementioning

confidence: 99%

“…By sensing ER stress, IRE1α self-activates by autophosphorylation and splices X-box binding protein 1 (XBP1) mRNA independent of the spliceosome. We previously elucidated that electrophiles such as MeHg and nitric oxide cause a decline in XBP1 mRNA splicing and induce apoptosis in vitro (Hiraoka et al 2017;Nakato et al 2015). Additionally, UPR dysfunction has been suggested to contribute to the onset of neurodegenerative disease (Remondelli and Renna 2017).…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain

et al. 2021

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Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures a specific area of the brain. MeHg-mediated neurotoxicity is believed to be caused by oxidative stress and endoplasmic reticulum (ER) stress, but the mechanism by which those stresses lead to neuronal loss is unclear. Here, by utilizing the ER stress-activated indicator (ERAI) system, we investigated the signaling alterations in the unfolded protein response (UPR) prior to neuronal apoptosis in the mouse brain. In ERAI transgenic mice exposed to MeHg (25 mg/kg, S.C.), the ERAI signal, which indicates activation of the cytoprotective pathway of the UPR, was detected in the brain. Interestingly, detailed ex vivo analysis showed that the ERAI signal was localized predominantly in neurons. Time course analysis of MeHg exposure (30 ppm in drinking water)showed that whereas the ERAI signal was gradually attenuated at the late phase after increasing at the early phase, activation of the apoptotic pathway of the UPR was enhanced in proportion to the exposure time. These results suggest that MeHg induces not only ER stress but also neuronal cell death via a UPR shift. UPR modulation could be a therapeutic target for treating neuropathy caused by electrophiles similar to MeHg.

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Modulation of Unfolded Protein Response by Methylmercury

Cited by 13 publications

References 20 publications

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain

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