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The Anti-Neuron-Specific Enolase Antibody Induced Neuronal Cell Death in a Novel Fashion

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Abstract

Suppression of ubiquitin proteasome pathway (UPP) and stimulation of caspase-3 are involved in neurodegeneration. Can UPP activators and caspase-3 inhibitors ameliorate neurodegeneration? Here, we found a novel neuronal cell death accompanied with UPP activation and caspase-3 inhibition. Recently, plasmalemmal neuron-specific enolase (NSE) has been identified as one of membrane targets of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 induces neuronal apoptosis via activating caspase-3 and inactivating UPP, whereas the anti-NSE antibody inactivated caspase-3, activated UPP, and caused neuronal cell death. The anti-NSE antibody activated caspase-1 (pyroptosis marker), but not condense chromatin (apoptosis marker). The anti-NSE antibody declined intracellular level of ATP, which is not altered in pyroptosis. The intracellular level of calcium is elevated in necrosis and pyroptosis, but its chelator did not ameliorate the neurotoxicity of anti-NSE. Thiol antioxidants such as N-acetyl cysteine and glutathione reduced the neurotoxicity of 15d-PGJ2 but enhanced that of the anti-NSE antibody. The anti-NSE antibody incorporated propidium iodide into neurons through the disrupted plasma membrane, which are not observed in ferroptosis and autophagic cell death. Thus, the anti-NSE antibody induced neuronal cell death in a novel fashion distinguished from necrosis, necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagic cell death.

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Acknowledgments

The authors would like to thank Mr. Hiroaki Kumagai for supporting this study.

Funding

The work presented in the submitted manuscript was funded by Grant-in-Aid 17K08327 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Author notes

  1. Yasuhiro Yamamoto and Hiromi Koma contributed equally to this work.

Authors and Affiliations

  1. Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji, Hyogo, 670-8524, Japan

    Yasuhiro Yamamoto, Hiromi Koma & Tatsurou Yagami

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  1. Yasuhiro Yamamoto
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  3. Tatsurou Yagami
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Correspondence to Tatsurou Yagami.

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Supplemental data 1

Antibodies against NSE and HSP70 reduced inactive pro-caspase-1. Neurons were treated without or with normal goat IgG (400 ng/mL), anti-NSE antibody (400 ng/mL), anti-HSP70 antibody (400 ng/mL) or 15d-PGJ2 (3 or 4 μM) for 24 h. Pro-caspase-1 and caspase-1 of neuronal cell lysates were separated by SDS-PAGE, and detected by immunoblotting with anti-procaspase-1 antibody (AI 1156 kb)

Supplemental data 2

Effect of BAPTA-AM on the neurotoxicity of antibodies against NSE and HSP70. Neurons (7DIV) were treated with BAPTA-AM at the indicated concentrations in the absence (circles) or presence of 200 ng/mL anti-NSE antibody (triangles) and 200 ng/mL anti-HSP70 antibody (squares) for 48 h. Cell viabilities were determined by MTT reducing activity. Data are expressed as means ± SE. (n = 3). *P < 0.05 and **P < 0.01, compared with control (AI 1191 kb)

Supplemental data 3

Effects of MAP kinase inhibitors on the neurotoxicity of antibodies against NSE and HSP70. Neurons were treated with U0126 (A), SB202190 (B) or SP600125 (C) at the indicated concentrations in the absence (circles; control) or presence of normal goat IgG (triangles; 200 ng/mL) or the anti-HSP antibody (squares; 200 ng/mL). (D) Neurons were treated with SP600125 at the indicated concentrations in the absence (open circles; control) or presence of normal goat IgG (open triangles; 200 ng/mL), the anti-NSE antibody (open squares; 200 ng/mL) or 15d-PGJ2 (closed circles; 3.5 μM). Cell viabilities were determined by MTT reducing activity. Data are expressed as means ± SD. (n = 3). *P < 0.05, **P < 0.01, compared with the normal goat IgG alone and #P < 0.05, ##P < 0.01, compared with the anti-HSP70 antibody alone (AI 1232 kb)

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Yamamoto, Y., Koma, H. & Yagami, T. The Anti-Neuron-Specific Enolase Antibody Induced Neuronal Cell Death in a Novel Fashion. Mol Neurobiol 57, 2265–2278 (2020). https://doi.org/10.1007/s12035-020-01876-8

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