Virus-induced RGMa expression drives neurodegeneration in HTLV-1–associated myelopathy
Natsumi Araya, Makoto Yamagishi, Makoto Nakashima, Naomi Asahara, Kazuhiro Kiyohara, Satoko Aratani, Naoko Yagishita, Erika Horibe, Izumi Ishizaki, Toshiki Watanabe, Tomoo Sato, Kaoru Uchimaru, Yoshihisa Yamano
Natsumi Araya, Makoto Yamagishi, Makoto Nakashima, Naomi Asahara, Kazuhiro Kiyohara, Satoko Aratani, Naoko Yagishita, Erika Horibe, Izumi Ishizaki, Toshiki Watanabe, Tomoo Sato, Kaoru Uchimaru, Yoshihisa Yamano
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Research Article Infectious disease Neuroscience

Virus-induced RGMa expression drives neurodegeneration in HTLV-1–associated myelopathy

Abstract

Human T-lymphotropic virus type 1–associated (HTLV-1–associated) myelopathy (HAM, also known as tropical spastic paraparesis) is a rare neurodegenerative disease with largely elusive molecular mechanisms, impeding targeted therapeutic advancements. This study aimed to identify the critical molecule responsible for neuronal damage in HAM, its source, and the regulatory mechanisms controlling its expression. Utilizing patient-derived cells and established cell lines, we discovered that HTLV-1 Tax, in conjunction with specificity protein 1 (Sp1), enhanced the expression of repulsive guidance molecule A (RGMa), a protein known to contribute to neuronal damage. RGMa expression was specifically upregulated in HTLV-1–infected cells from patients with HAM, particularly in those expressing HTLV-1 Tax. Furthermore, in CD4+ cells from patients with HAM, the level of H3K27me3 methylation upstream of the RGMA gene locus was reduced, making RGMA more prone to constitutive expression. We demonstrated that HTLV-1–infected cells in HAM inflict neuronal damage via RGMa. Crucially, the neutralizing antibody against RGMa, unasnemab (MT-3921), effectively mitigated this damage in a dose-responsive manner, highlighting RGMa’s pivotal role in neuronal damage and its potential as a therapeutic target for alleviating neuronal damage in HAM.

Authors

Natsumi Araya, Makoto Yamagishi, Makoto Nakashima, Naomi Asahara, Kazuhiro Kiyohara, Satoko Aratani, Naoko Yagishita, Erika Horibe, Izumi Ishizaki, Toshiki Watanabe, Tomoo Sato, Kaoru Uchimaru, Yoshihisa Yamano

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Figure 4

Tax and Sp1 cooperatively enhance RGMA transcription.

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Tax and Sp1 cooperatively enhance RGMA transcription. (A) Coactivation o...
(A) Coactivation of the RGMA transcriptional regulatory region by Sp1 and Tax. HEK293 cells were transfected with 10 ng of RGMA-Luc reporter plasmid, 300 ng of Sp1 expression plasmid, and 0–300 ng of either Tax or Tax C29A expression plasmid, as indicated. Values were normalized to β-galactosidase activity as an internal control (n = 4). (B) ChIP-qPCR analysis of the predicted Sp1 binding region upstream of the RGMA locus in JPX9 cells following treatment with 20 μM CdCl2 for 48 hours. Tax and Sp1 binding were evaluated in comparison to mouse IgG and rabbit IgG, respectively. The immunoprecipitated DNA was normalized to input DNA (n = 4). Data are shown as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Dunnett’s multiple-comparison test (A) or 2-sided Student’s t test (B). Experiments were performed in triplicate.