Hasiera » Seminars » Aβ oligomers cause dysregulation of RNA dynamics and translational activity in oligodendrocytes

Aβ oligomers cause dysregulation of RNA dynamics and translational activity in oligodendrocytes

Adhara Gaminde Blasco

Laboratory of Neurobiology, ACHUCARRO

03 Feb 2023 13:30

Aketxe Room, Sede Building, Leioa

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Oligodendrocyte dysfunction, myelin degeneration and alterations in the white matter structures are events in Alzheimer’s disease (AD) that might lead to cognitive deficits. One of the hallmarks of AD is the presence of extracellular aggregates of amyloid beta peptide (Aβ), and Aβ oligomers (Abo) have been proposed to induce changes in oligodendrocytes and myelin. However, the effects of Abo on oligodendrocytes are not fully understood. Here, we report that RNA metabolism and proteostasis regulation mechanisms significantly affected by Abo in oligodendrocytes.

To gain more comprehensive insights into the impact of Abo on oligodendrocytes, we performed RNA-seq in primary cultured cells treated with Abo and controls. The differential expression analysis revealed that Abo significantly altered signaling pathways associated with RNA metabolism and ribonucleoprotein (RBP) complex. To obtain a mechanistic understating of these cellular processes, we focus our study on heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), a key regulator of RNA metabolism that mediates intracellular trafficking of MBP and MOBP. Indeed, western blot and immunocytochemistry analysis showed that hnRNP A2 was upregulated in oligodendrocytes of AD patients and in vitro with Abo treatment. Using RNA-immunoprecipitation (RIP)-seq, we identified components of RNA-splicing, -processing and -binding, translational regulation and ribonucleoprotein complex biogenesis, as A2-interacting RNAs in oligodendrocytes. Upon Abo treatment, the A2-interactome was significantly modified. Accordingly, we showed that overexpression of hnRNP A2 overlapped with an increase in number and dynamics of mRNA transport granules and local translation of MBP and MOBP. Interestingly, upregulation of MBP led to changes in calcium homeostasis, and translation in cultured oligodendrocytes, and myelination in the triple transgenic AD mouse model.

Taken together, these results suggest that Aβo could alter oligodendrocyte basic functions through modification of hnRNP A2 interactome, with potential consequences in the oligodendrocyte-neuron interactions.