Figures & data
Table 1 Clinical and pathological features of progressive MS, HAM/TSP, and HSP
Figure 1 Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS) immunoglobulin G (IgG) react with the same epitope in M9. Schematic of heterogeneous nuclear ribonucleoprotein (hnRNP) A1 shows the RNA-binding domains (RBDs), the RGG domain, and M9. Overlapping protein-fragment experiments showed HAM/TSP and MS IgG reacted with an epitope (amino acids [AA] 293-GQYFAKPRNQGG-304, red box), which is contained within the M9 sequence (AA 268–305).Citation11,Citation127
![Figure 1 Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS) immunoglobulin G (IgG) react with the same epitope in M9. Schematic of heterogeneous nuclear ribonucleoprotein (hnRNP) A1 shows the RNA-binding domains (RBDs), the RGG domain, and M9. Overlapping protein-fragment experiments showed HAM/TSP and MS IgG reacted with an epitope (amino acids [AA] 293-GQYFAKPRNQGG-304, red box), which is contained within the M9 sequence (AA 268–305).Citation11,Citation127](/cms/asset/b116ddd2-38c1-49e9-9938-d8214a8d0ccf/dnnd_a_38353_f0001_c.jpg)
Figure 2 Genes identified by Gene Ontology are directly related to heterogeneous nuclear ribonucleoprotein (hnRNP) A1 function. The gene categories and some individual genes affected by the anti-M9 antibodies are shown in red type. The complete M9 sequence (amino acids [AA] 268–305) is elongated for emphasis and bordered by the black lines within hnRNP A1. Transportin binds the M9 region at AA 263–289. AA 293–304, which are recognized by the multiple sclerosis and human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis immunoglobulin G anti-M9 immune response, are not bound to transportin, and thus are available for antibody binding.Citation11
![Figure 2 Genes identified by Gene Ontology are directly related to heterogeneous nuclear ribonucleoprotein (hnRNP) A1 function. The gene categories and some individual genes affected by the anti-M9 antibodies are shown in red type. The complete M9 sequence (amino acids [AA] 268–305) is elongated for emphasis and bordered by the black lines within hnRNP A1. Transportin binds the M9 region at AA 263–289. AA 293–304, which are recognized by the multiple sclerosis and human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis immunoglobulin G anti-M9 immune response, are not bound to transportin, and thus are available for antibody binding.Citation11](/cms/asset/bdda82f7-9fb0-4632-9055-4e4cdb7761b8/dnnd_a_38353_f0002_c.jpg)
Table 2 Gene clusters (color coded) identified by a text-mining database using clinical search terms following anti-hnRNP A1-M9 antibody transfection into neurons (column 1, color coded) and their primary functions (columns 2–7)
Figure 3 Spastin mRNA is bound to heterogeneous nuclear ribonucleoprotein (hnRNP) A1 in neuronal cells. Upper panel: agarose gel. Compared to the neuronal lysate without immunoprecipitation or input (lane 3), there is an enriched spastin mRNA signal following immunoprecipitation with anti-hnRNP A1 mouse monoclonal antibodies (lane 1). In contrast, spastin mRNA was not isolated following immunoprecipitation with a nonspecific control antibody – mouse IgG (lane 2). Lane 4 used spastin primers without lysate (control for DNA contamination). Lower panel: the image was analyzed using ImageQuant software, which provided relative fluorescent intensity of the bands.
Figure 4 Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 localization following TNF-α exposure in neurons. Without TNF-α exposure, hnRNP A1 is localized to nuclei (*) in dNT-2 neurons (left panels) (blue nuclear stain is diamidino-2-phenylindole; green stain is immunohistochemistry using an anti-hnRNP A1 antibody). Following exposure to TNF-α (400 ng/mL, 50 mM glutamate, 30 minutes), hnRNP A1 is also found in the cytoplasm (arrowheads) and neuronal processes (arrow) of neurons (lower right panel).
Figure 5 Potential contribution of the anti-heterogeneous nuclear ribonucleoprotein (hnRNP) A1 M9 immune response to neurodegeneration in immune-mediated neurological disease. Multiple sclerosis and human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis patients develop antibodies to an epitope contained within the M9 region of hnRNP A1 (box). hnRNP A1 has been shown to interact molecularly with spastin RNA and protein (box and figure). The anti-M9 immune response altered spastin RNA levels, which may alter spastin function at multiple sites within neurons (blue boxes). The combination of proinflammatory cytokines and the anti-M9 immune response might contribute to neurodegeneration in immune-mediated neurological disease.
