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

Abstract

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.

hnRNP A1 dysfunction in oligodendrocytes contributes to the pathogenesis of multiple sclerosis

“…Collectively, our data highlight an important role for hnRNP A1 in proper OL functioning and survival and suggest a potential mechanism of OL damage and death in MS that involves hnRNP A1 dysfunction. This adds to our ongoing work (Anees et al, 2021; Li et al, 2021; Libner et al, 2020; Salapa et al, 2018; Salapa, Hutchinson, et al, 2020; Salapa, Libner, & Levin, 2020) that hnRNP A1 dysfunction in neurons contributes to neurodegeneration in MS and its models. Along with the data presented here, in which we show that hnRNP A1 dysfunction in OLs leads to OL death, damage and subsequent demyelination, suggest that together, hnRNP A1 dysfunction in both OLs and neurons combine to contribute to central nervous system damage and subsequent disability in MS. Future studies should expand on the role hnRNP A1 dysfunction may play in the ability of OLs to properly maintain or produce new myelin.…”

“…Collectively, our data highlight an important role for hnRNP A1 in proper OL functioning and survival and suggest a potential mechanism of OL damage and death in MS that involves hnRNP A1 dysfunction. This adds to our ongoing work (Anees et al, 2021;Li et al, 2021;Libner et al, 2020;Salapa et al, 2018;Salapa, Hutchinson, et al, 2020;) that hnRNP A1 dysfunction in neurons contributes to neurodegeneration in MS and its models.…”

“…Mature OL loss also peaked at disease onset while the number of OPCs increased throughout disease, suggestive of OPC migration to restore mature OLs. Several studies have shown a relationship between RBP dysfunction and pro‐inflammatory cytokines (Correia et al, 2015; Li et al, 2021; Salapa et al, 2018). Furthermore, pro‐inflammatory cytokines, such as IFNγ, have been shown to contribute to OL death in MS and relevant models (Lin et al, 2005; Pouly et al, 2000; Vartanian et al, 1995; Way et al, 2015).…”

“…Previous studies illustrate a role for pro-inflammatory cytokines in inducing dysfunctional RBPs (Correia et al, 2015;Li et al, 2021;Salapa et al, 2018). Since it is well-documented that IFNγ-producing T cells are a driver of MS and EAE pathology (Fletcher et al, 2010) 5a-c).…”

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies

“…In fact, it is well-known that RBPs are key players in the RNA metabolism especially in neurons where they are particularly expressed [ 96 ]. Recently, it has been demonstrated that pro-inflammatory mediators, such as IFN-γ and TNF-α, are able to trigger hnRNP A1 mislocalization and stress granule formation in murine primary neuron culture, with consequently neurite damage [ 97 ]. Specifically, SAFA (also known as hnRNP U) was found to be involve in protecting cells from viral infections, since it acts at a nuclear sensor for viral dsRNA and is able to trigger the activation of super-enhancer of anti-viral gene expression, such as IFNB1 [ 98 ].…”