Progress in Neurobiology: Pathogenic Oligomeric Tau alters Neuronal RNA Processes through the Formation of Nuclear Heteromeric Amyloids with RNA-Binding Protein Musashi1 (Penalva)

Alzheimer’s disease (AD) is marked by cytoplasmic proteinopathies, primarily involving misfolded Tau protein. Pathogenic Tau species, such as soluble oligomers and fibrils, disrupt RNA metabolism, though the mechanisms are unclear. Recent research indicates that RNA has a crucial role in Tau aggregation. Our study builds on this by noting significant co-deposition of RNA-Binding Proteins (RBPs) with Tau in AD and Frontotemporal dementia (FTLD) brains. We use molecular and cellular techniques to investigate the interaction between RNA dynamics and Tau aggregation, focusing on the localization and aggregation of Tau and RBPs, particularly Musashi (MSI), within neuronal nuclei. Through cyto-fluorometric, biochemical, and cellular assays, we reveal the importance of Tau/RBP interplay in primary cortical neurons expressing wild-type and mutant Tau. Pathogenic Tau oligomers alter MSI protein localization and function, causing cytoplasmic and nuclear aggregation. Mass spectrometry of the MSI1 nuclear interactome in Tau models shows disrupted RNA metabolism pathways, including ribosomal biogenesis, RNA splicing, and protein folding. Moreover, the RNA immunoprecipitation assay revealed a remarkable impact of mutant P301L Tau on MSI1’s ability to bind RNA targets. These findings highlight potential targets for early neurodegenerative therapeutic interventions.