RNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction

Mauro Montalbano, Salome McAllen, Nicha Puangmalai, Urmi Sengupta, Nemil Bhatt, Omar D. Johnson, Michael G. Kharas and Rakez Kayed ()
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Mauro Montalbano: University of Texas Medical Branch
Salome McAllen: University of Texas Medical Branch
Nicha Puangmalai: University of Texas Medical Branch
Urmi Sengupta: University of Texas Medical Branch
Nemil Bhatt: University of Texas Medical Branch
Omar D. Johnson: University of Texas Medical Branch
Michael G. Kharas: Memorial Sloan Kettering Institute Cancer Center
Rakez Kayed: University of Texas Medical Branch

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer’s disease (AD). However, the role of MSI and tau interaction in their aggregation process and its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models. We observed that formation of pathologically relevant protein inclusions was driven by the aberrant interactions between MSI and tau in the nuclei associated with age-dependent extracellular depositions of tau/MSI complexes. Furthermore, tau and MSI interactions induced impairment of nuclear/cytoplasm transport, chromatin remodeling and nuclear lamina formation. Our findings provide mechanistic insight for pathological accumulation of MSI/tau aggregates providing a potential basis for therapeutic interventions in neurodegenerative proteinopathies.

Date: 2020
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DOI: 10.1038/s41467-020-18022-6

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