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

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

doi:10.3390/ijms21134571

Cited by 15 publications

(9 citation statements)

References 145 publications

(203 reference statements)

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“…RBP dysfunction contributes to neurodegeneration in a number of diseases including MS [248][249][250][251][252][253]. The RBPs heterogenous nuclear ribonucleoprotein A1 (hnRNP A1) and transactive response DNA binding protein 43 (TDP-43) are mislocalized within the ventral spinal cord neurons during chronic EAE, which is correlated with axonal damage and neuronal loss [246,247,254].…”

Section: Cytokine Induced Rna Binding Protein Dysfunctionmentioning

confidence: 99%

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

Kamma

Lasisi

Libner

et al. 2022

J Neuroinflammation

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There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing–remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood–brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.

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Section: Cytokine Induced Rna Binding Protein Dysfunctionmentioning

confidence: 99%

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

Kamma

Lasisi

Libner

et al. 2022

J Neuroinflammation

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“…We have summarized the classical as well as emerging hallmark functions of RBPs in Figure 1. Given their widespread impact on gene expression and signaling networks, mutations or defects in the expression or localization of RBPs can cause a broad range of diseases, e.g., neurodegeneration, obesity, hypertension, and cancer [55,[89][90][91][92][93][94][95][96]. In the next paragraph, we will highlight selected examples of RBPs that have been shown to contribute to the malignancy of oral cancer, especially its metastatic features.…”

Section: General Functions and Mechanisms Of Rna-binding Proteinsmentioning

confidence: 99%

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

Weiße

Rosemann

Krauspe

et al. 2020

IJMS

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Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.

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“…In neurons, precise regulation of protein homeostasis is required to maintain the highly polarized state ( Thelen and Kye, 2019 ), in which RBPs play a key role. Dysfunction of RBPs has recently been established as a contributing factor to neuronal pathology in neurodegenerative diseases, leading to wide scale disturbances in RNA processing and activity ( Belzil et al, 2013 ; Ling et al, 2013 ; Libner et al, 2020 ). HnRNP A1 is highly expressed in neurons and dysfunctional hnRNP A1 is a hallmark of several neurologic diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis, frontotemporal lobar dementia (FTLD), and recently, multiple sclerosis (MS; Donev et al, 2007 ; Kashima et al, 2007 ; Levin et al, 2017 ; Salapa et al, 2018 , 2020a , b ; Clarke et al, 2021a ; Low et al, 2021 ).…”

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

Salapa

Thibault

et al. 2021

eNeuro

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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.

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

Cited by 15 publications

References 145 publications

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

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

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