Dysfunctional RNA‐binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice

Salapa, Hannah E.; Libner, Cole D.; Levin, Michael C.

doi:10.1002/jnr.24554

Cited by 19 publications

(36 citation statements)

References 57 publications

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“…These investigators also reported that neurons in a region of an MS brain (in which no pathology was described) had nuclear depletion and cytoplasmic mislocalization of hnRNP A1, which was aggregated in stress granules. A more recent publication by Salapa et al 29 found mislocalization of hnRNP A1 and TDP-43 in spinal cord neurons in experimental allergic encephalomyelitis; the hnRNP A1 mislocalization correlated with the clinical score and presence of infiltrates of CD3 + cells secreting interferon-γ.…”

Section: Discussionmentioning

confidence: 93%

RNA-binding protein altered expression and mislocalization in MS

Kitajima

Sonobe

Ghadge

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo determine whether there are nuclear depletion and cellular mislocalization of RNA-binding proteins (RBPs) transactivation response DNA-binding protein of 43 kDa (TDP-43), fused in sarcoma (FUS), and polypyrimidine tract–binding protein (PTB) in MS, as is the case in amyotrophic lateral sclerosis (ALS) and oligodendrocytes infected with Theiler murine encephalomyelitis virus (TMEV), we examined MS lesions and in vitro cultured primary human brain–derived oligodendrocytes.MethodsNuclear depletion and mislocalization of TDP-43, FUS, and PTB are thought to contribute to the pathogenesis of ALS and TMEV demyelination. The latter findings prompted us to investigate these RBPs in the demyelinated lesions of MS and in in vitro cultured human brain–derived oligodendrocytes under metabolic stress conditions.ResultsWe found (1) mislocalized TDP-43 in oligodendrocytes in active lesions in some patients with MS; (2) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; (3) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; and (4) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared with optimal culture conditions.ConclusionTDP-43 has been found to have a key role in oligodendrocyte function and viability, whereas PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.

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Section: Discussionmentioning

confidence: 93%

RNA-binding protein altered expression and mislocalization in MS

Kitajima

Sonobe

Ghadge

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…Cortical neuron phenotypes 6 and 7 have the greatest degree of cytoplasmic staining (representative of nucleocytoplasmic mislocalization), which has been strongly associated with neurodegeneration and neuronal injury in other neurological diseases and their models. 10,14,[21][22][23][24] Remarkably, we could not find any of Figure 2. Differential distribution of TDP-43 phenotypes in control and MS normal appearing cortex.…”

Section: Discussionmentioning

confidence: 65%

“…We have previously shown that proinflammatory cytokines, antibodies to hnRNP A1, and MS-associated mutations within hnRNP A1 lead to its mislocalization from nucleus to cytoplasm in in vitro models. 2,34,35 We and others have also demonstrated that hnRNP A1 and TDP-43 neuronal mislocalization is a prominent feature in mouse models of MS. 11,36 Particularly, we found that the degree of hnRNP A1 mislocalization positively correlated with experimental autoimmune encephalomyelitis disease severity and negatively correlated with neuronal cell count. 36 This suggests that the severity of RBP mislocalization may be related to neurodegeneration and disease progression.…”

Section: Discussionmentioning

confidence: 74%

“…[3][4][5][6][7][8][9] Common features of dysfunctional RBPs in these diseases include mislocalization of the RBP from its homeostatic nuclear location to the cytoplasm and the formation of protein aggregates in the cytoplasm of cells. We and others have shown that dysfunctional RBPs, including hnRNP A1 and TDP-43, are prominent pathological features in relevant animal models of MS. 10,11 We demonstrated that TDP-43 and hnRNP A1 mislocalization are prevalent in spinal cord neurons of animals with experimental autoimmune encephalomyelitis. Additional analyses revealed that hnRNP A1 mislocalization correlated with disease severity, CD3 + immune cell infiltrates, SMI-32 staining, a marker of neurodegeneration, and neuronal cell death.…”

Section: Introductionmentioning

confidence: 91%

“…Additional analyses revealed that hnRNP A1 mislocalization correlated with disease severity, CD3 + immune cell infiltrates, SMI-32 staining, a marker of neurodegeneration, and neuronal cell death. 10 Given these data suggesting that dysfunctional RBP biology may contribute to neurodegeneration in a model of MS and our previous observations in human tissue, we sought to determine whether hnRNP A1 and TDP-43 mislocalization are features of neurons in MS cortex. We have found an increased incidence of differential distribution of the RBPs hnRNP A1 and TDP-43 in normal appearing cortical neurons from 12 MS cases as compared to controls.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex

Salapa

Hutchinson

Popescu

et al. 2020

Ann Clin Transl Neurol

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Objective: Neurodegeneration is thought to be the primary cause of neurological disability in multiple sclerosis (MS). Dysfunctional RNA-binding proteins (RBPs) including their mislocalization from nucleus to cytoplasm, stress granule formation, and altered RNA metabolism have been found to underlie neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia. Yet, little is known about the role of dysfunctional RBPs in the pathogenesis of neurodegeneration in MS. As a follow-up to our seminal finding of altered RBP function in a single case of MS, we posited that there would be evidence of RBP dysfunction in cortical neurons in MS. Methods: Cortical neurons from 12 MS and six control cases were analyzed by immunohistochemistry for heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA-binding protein-43 (TDP-43). Seven distinct neuronal phenotypes were identified based on the nucleocytoplasmic staining of these RBPs. Statistical analyses were performed by analyzing each phenotype in relation to MS versus controls. Results: Analyses revealed a continuum of hnRNP A1 and TDP-43 nucleocytoplasmic staining was found in cortical neurons, from neurons with entirely nuclear staining with little cytoplasmic staining in contrast to those with complete nuclear depletion of RBPs concurrent with robust cytoplasmic staining. The neuronal phenotypes that showed the most nucleocytoplasmic mislocalization of hnRNP A1 and TDP-43 statistically distinguished MS from control cases (P < 0.01, P < 0.001, respectively). Interpretation: The discovery of hnRNP A1 and TDP-43 nucleocytoplasmic mislocalization in neurons in MS brain demonstrate that dysfunctional RBPs may play a role in neurodegeneration in MS, as they do in other neurological diseases.

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Antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 contribute to neuronal cell loss in an animal model of multiple sclerosis

Libner

Salapa

Hutchinson

et al. 2020

J of Comparative Neurology

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Neurodegeneration, including loss of neurons and axons, is a feature of progressive forms of multiple sclerosis (MS). The mechanisms underlying neurodegeneration are mostly unknown. Research implicates autoimmunity to nonmyelin self‐antigens as important contributors to disease pathogenesis. Data from our lab implicate autoimmunity to the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a possible mechanism of neurodegeneration in MS. MS patients make antibodies to hnRNP A1, which have been shown to lead to neuronal dysfunction in vitro. Using an animal model of MS, experimental autoimmune encephalomyelitis (EAE), we show here that injection of anti‐hnRNP A1 antibodies, in contrast to control antibodies, resulted in worsened disease and increased neurodegeneration. We found a reduction of NeuN+ neuronal cell bodies in areas of the ventral gray matter of the spinal cord where anti‐hnRNP A1 antibodies localized. Neurons displayed increased levels of hnRNP A1 nucleocytoplasmic mislocalization and stress granule formation, both markers of neuronal injury. Anti‐hnRNP A1 antibodies were found to surround neuronal cell bodies and interact with CD68+ immune cells via Fc receptors. Additionally, anti‐hnRNP A1 antibodies were found within neuronal cell bodies including those of the ventral spinocerebellar tract (VSCT), a tract previously shown to undergo neurodegeneration in anti‐hnRNP A1 antibody injected EAE mice. Finally, both immune cells and neurons showed increased levels of inducible nitric oxide synthase, another indicator of cell damage. These findings suggest that autoimmunity to RBPs, such as hnRNP A1, play a role in neurodegeneration in EAE with important implications for the pathogenesis of MS.

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Dysfunctional RNA‐binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice

Cited by 19 publications

References 57 publications

RNA-binding protein altered expression and mislocalization in MS

RNA-binding protein altered expression and mislocalization in MS

Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex

Antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 contribute to neuronal cell loss in an animal model of multiple sclerosis

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