TAU OLIGOMERS MEDIATE AGGREGATION OF RNA-BINDING PROTEINS MUSASHI1- AND MUSASHI2-INDUCING NUCLEAR MEMBRANE ALTERATION IN ALZHEIMER’S DISEASE

Abstract

RNA-Binding Proteins (RBPs) accumulate and aggregate in different neurodegenerative diseases, including Alzheimer's disease (AD). The Musashi (MSI) family is a group of RBPs which includes two homologous proteins, Musashi1 and Musashi2 (MSI1 and MSI2). MSI proteins are known to be expressed in neuronal stem cells and even at elevated levels in different types of cancers; however, there is no data reported on their functions in AD. Recent studies have shown that different RBPs, such as TDP-43, FUS, and TIA-1, form toxic oligomers that interact with tau and potentially influence its toxicity in the neurons through stress granules (SGs) alteration. We previously described, for the first time, that MSI1 and MSI2 are prone to form toxic aggregates in vitro. Additionally, we observed oligomeric MSI proteins in AD bran tissues, which also co-localized with tau oligomers. In the current report we investigated the mechanisms how MSI proteins and tau interact using a well-established tau-inducible cell model (iHEK). We used WT tau iHEK and P301L mutant tau iHEK cells to test whether MSI contributes to the aggregation of toxic tau oligomers and whether these tau forms and their aggregates can affect endogenous MSI cellular localization and function. We found that tau co-localized and accumulated with MSI in different cellular compartments, in particular, in the cytoplasm and nuclei, altering the nuclear transport of MSI1 and MSI2. Such cellular effects caused by P301L mutant tau were much stronger than WT tau that also associated with an increment in size and density of nuclear MSI/tau foci. We also report the novel finding that tau oligomers interaction with MSI1 and MSI2 resulted in the formation of distinct nuclear macro-molecular aggregates. Moreover, the formation of tau /MSI aggregates induced a decrement of LaminA/C and LaminB1 gene and protein levels inducing nuclear membrane instability. Our novel findings suggest that MSI proteins play a role in cellular dysfunction and AD pathogenesis. Our data highlight a possible mechanism of neurodegeneration mediated by aggregated MSI proteins and tau oligomers, opening an interesting opportunity to address new mechanistic insights.