Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 98, Issue 4, Pages 704-717Publisher
WILEY
DOI: 10.1002/jnr.24554
Keywords
experimental autoimmune encephalomyelitis; heterogeneous nuclear ribonucleoprotein A1; multiple sclerosis; RNA-binding protein; >; >; >; >; >; >; >; >; >; >; >; >; >; >; stress granules; TAR-DNA binding protein-43
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Funding
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
- Saskatchewan Health Research Foundation, Saskatoon, Saskatchewan, Canada [4244]
- Saskatoon City Hospital Foundation, Saskatoon, Saskatchewan, Canada
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Altered stress granule (SG) and RNA-binding protein (RBP) biology have been shown to contribute to the pathogenesis of several neurodegenerative diseases, yet little is known about their role in multiple sclerosis (MS). Pathological features associated with dysfunctional RBPs include RBP mislocalization from its normal nuclear location to the cytoplasm and the formation of chronic SGs. We tested the hypothesis that altered SG and RBP biology might contribute to the neurodegeneration in experimental autoimmune encephalomyelitis (EAE). C57BL/6 female mice were actively immunized with MOG(35-55) to induce EAE. Spinal cords were examined for mislocalization of the RBPs, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA binding protein-43 (TDP-43), SGs, neurodegeneration (SMI-32), T cells (CD3), and macrophages (CD68). In contrast to naive mice, mice with EAE showed SG formation (p < 0.0001) and mislocalization of hnRNP A1 (p < 0.05) in neurons of the ventral spinal cord gray matter, which correlated with clinical score (R = 0.8104, p = 0.0253). In these same areas, there was a neuronal loss (p < 0.0001) and increased SMI-32 immunoreactivity (both markers of neurodegeneration) and increased staining for CD3(+) T cells and IFN-gamma. These findings recapitulate the SG and RBP biology and markers of neurodegeneration in MS tissues and suggest that altered SG and RBP biology contribute to the neurodegeneration in EAE, which might also apply to the pathogenesis of MS.
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