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

Abstract

Oligodendrocyte (OL) damage and death are prominent features of multiple sclerosis (MS) pathology, yet mechanisms contributing to OL loss are incompletely understood. Dysfunctional RNA binding proteins (RBPs), hallmarked by nucleocytoplasmic mislocalization and altered expression, have been shown to result in cell loss in neurologic diseases, including in MS. Since we previously observed that the RBP heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was dysfunctional in neurons in MS, we hypothesized that it might also contribute to OL pathology in MS and relevant models. We discovered that hnRNP A1 dysfunction is characteristic of OLs in MS brains. These findings were recapitulated in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, where hnRNP A1 dysfunction was characteristic of OLs, including oligodendrocyte precursor cells and mature OLs in which hnRNP A1 dysfunction correlated with demyelination. We also found that hnRNP A1 dysfunction was induced by IFNγ, indicating that inflammation influences hnRNP A1 function. To fully understand the effects of hnRNP A1 dysfunction on OLs, we performed siRNA knockdown of hnRNP A1, followed by RNA sequencing.RNA sequencing detected over 4000 differentially expressed transcripts revealing alterations to RNA metabolism, cell morphology, and programmed cell death pathways. We confirmed that hnRNP A1 knockdown was detrimental to OLs and induced apoptosis and necroptosis. Together, these data demonstrate a critical 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.

Amyloid-beta increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2 dependent RNA dynamics

“…In this study, we described for the first time the transcripts associated with hnRNP A2 in oligodendrocytes. In particular, in agreement with data described for hnRNP A1 (73), hnRNP A2 regulated genes associated with RNA biology, involved in RNA metabolism, processing and splicing, biogenesis of ribonucleoprotein complexes and translation regulation. Intriguingly, we observed that Aβ upregulates hnRNP A2 and disrupts its associated transcripts, leading to a weakening of interactions with over 50% of total mRNAs.…”

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

“…Alterations in RBP expression levels and function have been associated with neurological disorders (e.g. HNRNPA1 [ 45 ], MATR3 [ 46 , 47 ], TIA1 [ 48 ], and TARDBP [ 49 ] and brain tumour development (e.g. Musashi1 [ 8 , 50 , 51 ], SERBP1 [ 11 ], PTB [ 12 ] and HuR [ 17 ].…”

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

“…RNA binding proteins (RBPs) modulate numerous steps in gene expression and are particularly relevant in the nervous system (neurogenesis and brain development (Popper et al, 2021; Prashad and Gopal, 2021)), where they orchestrate changes in splicing, translation, and mRNA decay. Alterations in RBP expression levels and function have been associated with neurological disorders (e. g., HNRNPA1 (Jahanbazi Jahan-Abad et al, 2022), MATR3 (Johnson et al, 2014), TIA1 (Mackenzie et al, 2017), and TARDBP (Valdmanis et al, 2009)) and brain tumor development (e.g., Musashi1 (Toda et al, 2001; Galante et al, 2009; Velasco et al, 2019; Baroni et al, 2021a), SERBP1(Correa et al, 2016), PTB (McCutcheon et al, 2004) and HuR (Filippova et al, 2011; Guha et al, 2022a)). Modulation of their expression or target genes with specific inhibitors has started to be explored therapeutically (Hong, 2017).…”