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bioRxiv · 10.1101/2024.04.19.590214

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

Gaminde-Blasco, A.·Senovilla-Ganzo, R.·Balantzategi, U.·Garcia-Moreno, F.·Matute, C.·Baleriola, J.·Alberdi, E.
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Abstract

Oligodendrocyte dysfunction, myelin degeneration, and white matter structural alterations are critical events in Alzheimers disease (AD) that contribute to cognitive decline. A key hallmark of AD, A{beta} oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of A{beta}-exposed oligodendrocytes revealed widespread gene expression changes, particularly affecting pathways related to RNA localisation. Among the genes identified, we focused on Hnrnpa2/b1, the gene encoding the hnRNP A2 protein, which is essential for RNA transport and translation of myelin proteins. We confirmed aberrant upregulation of hnRNP A2 in hippocampal oligodendrocytes from post-mortem human brains of early-stage AD patients, A{beta}-injected mouse hippocampi and A{beta}-treated disrupting cells in vitro. RIP-seq analysis of the hnRNP A2 interactome revealed attenuated interactions with Hnrnpk and Hnrnpa2/b1, while interactions with Mbp and Mobp were enriched, suggesting changes in RNA metabolism of molecules associated with mRNA transport of myelin proteins. A{beta} increased the total number and dynamics of mRNA-containing granules, facilitating local translation of the myelin proteins MBP and MOBP and attenuating Ca2+ signalling. These findings suggest that A{beta} oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/590214v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@19e046eorg.highwire.dtl.DTLVardef@134f15corg.highwire.dtl.DTLVardef@d1f8aaorg.highwire.dtl.DTLVardef@11c97af_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

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Gaminde-Blasco, A., Senovilla-Ganzo, R., Balantzategi, U., Garcia-Moreno, F., Matute, C., Baleriola, J., Alberdi, E.. 2024-04-19. Amyloid-beta increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2 dependent RNA dynamics. https://doi.org/10.1101/2024.04.19.590214

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