RNA-binding protein altered expression and mislocalization in MS

Thibault

et al. 2021

eNeuro

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA binding protein (RBP) that is localized within neurons and plays crucial roles in RNA metabolism. Its importance in neuronal functioning is underscored from the study of its pathogenic features in many neurodegenerative diseases where neuronal hnRNP A1 is mislocalized from the nucleus to the cytoplasm resulting in loss of hnRNP A1 function. Here, we model hnRNP A1 loss-of-function by siRNA mediated knockdown in differentiated Neuro-2a cells. Through RNA sequencing (RNA-seq) followed by gene ontology (GO) analyses, we show that hnRNP A1 is involved in important biological processes, including RNA metabolism, neuronal function, neuronal morphology, neuronal viability, and stress granule (SG) formation. We further confirmed several of these roles by showing that hnRNP A1 knockdown results in a reduction of neurite outgrowth, increase in cell cytotoxicity and changes in SG formation. In summary, these findings indicate that hnRNP A1 loss-of-function contributes to neuronal dysfunction and cell death and implicates hnRNP A1 dysfunction in the pathogenesis of neurodegenerative diseases. Significance StatementHnRNP A1 plays a biologically important role in controlling gene expression and maintaining proper cellular functioning in neurons. Previous research has shown that many neurodegenerative diseases exhibit pathogenic features of hnRNP A1 dysfunction, whereby it is mislocalized from its homeostatic nuclear location to the cytoplasm resulting in loss of proper functioning. Here, we model hnRNP A1 loss-of-function in differentiated neuronal cells and show that it contributes to neuronal dysfunction and cell death. These 3 data are important because it underscores the importance of loss-of-function models and implicates hnRNP A1 dysfunction in the pathogenesis of neurodegenerative diseases.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Knock-Down of Heterogeneous Nuclear Ribonucleoprotein A1 Results in Neurite Damage, Altered Stress Granule Biology, and Cellular Toxicity in Differentiated Neuronal Cells

Anees

Thibault

et al. 2021

eNeuro

“…Subsets of Th cells, including Th1 and Th17, release pro-inflammatory cytokines and contribute to CNS damage in MS, while anti-inflammatory phenotypes, such as Th2 cells, may play a more protective role during disease [20][21][22][23][24]. Several studies suggest that the immune system may contribute to RNA-binding protein (RBP) dysfunction, which is a feature of neurons from MS cortex and relevant MS models [25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

“…Dysfunctional RBPs play a role in neurodegeneration in other neurologic diseases and have only recently been implicated in the pathogenesis of MS and its models [26][27][28][30][31][32][33][34][35]. Neuronal RBP dysfunction is characterized by the mislocalization of the RBP from its nuclear homeostatic location to the cytoplasm and the formation of cytoplasmic stress granules (SGs), which can trigger cellular toxicity [36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons

Hamilton

et al. 2021

Brain Sciences

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a significant neurodegenerative component. Dysfunctional RNA-binding proteins (RBPs) are causally linked to neuronal damage and are a feature of MS, including the mislocalization of the RBP heterogeneous nuclear ribonucleoprotein A1 (A1). Here, we show that primary neurons exposed to pro-inflammatory cytokines and anti-A1 antibodies, both characteristic of an MS autoimmune response, displayed increased A1 mislocalization, stress granule formation, and decreased neurite length, a marker of neurodegeneration. These findings illustrate a significant relationship between secreted immune factors, A1 dysfunction, and neuronal damage in a disease-relevant model system.

“…In a separate study, altered RBP biology was identified in oligodendrocytes and neurons of MS cases. These data found altered expression of the RBPs TDP-43 and polypyrimidine tract-binding protein 1 and 2 (PTB1 / PTB2) in cortical demyelinated lesions [130]. Considering the importance of TDP-43 and PTB1/2 in oligodendrocyte viability and neuronal differentiation, respectively, researchers hypothesized RBP dysfunction might contribute to cortical lesion damage and neurodegeneration in MS [130].…”

Section: Evidence In Neuronsmentioning

confidence: 96%

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

Libner

Levin

2020

IJMS

Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs.