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

Area of Science:

• Neuroimmunology
• Molecular Neuroscience
• Viral Pathogenesis

Background:

• Human T-lymphotropic virus type 1-associated myelopathy (HAM) is a rare neurodegenerative disorder with poorly understood molecular underpinnings.
• Current therapeutic strategies for HAM are limited due to the elusive mechanisms driving neuronal damage.

Purpose of the Study:

• To identify the key molecule responsible for neuronal injury in HAM.
• To elucidate the source and regulatory mechanisms of this molecule's expression in HAM pathogenesis.

Main Methods:

• Utilized patient-derived cells and cell lines for molecular analysis.
• Investigated the role of HTLV-1 Tax and Sp1 in regulating RGMa expression.
• Assessed H3K27me3 methylation levels in CD4+ cells from HAM patients.
• Evaluated the efficacy of the RGMa-neutralizing antibody unasnemab (MT-3921) in mitigating neuronal damage.

Main Results:

• HTLV-1 Tax and Sp1 synergistically enhance the expression of repulsive guidance molecule A (RGMa).
• RGMa is significantly upregulated in HTLV-1-infected cells from HAM patients, particularly those expressing Tax.
• Reduced H3K27me3 methylation at the RGMA locus in HAM patient CD4+ cells promotes constitutive RGMa expression.
• HTLV-1-infected cells induce neuronal damage through RGMa, which is dose-dependently inhibited by unasnemab.

Conclusions:

• RGMa is a critical mediator of neuronal damage in HAM, driven by HTLV-1 Tax and epigenetic modifications.
• Unasnemab, a neutralizing antibody against RGMa, demonstrates significant therapeutic potential for HAM by mitigating RGMa-induced neuronal injury.