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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Oligomeric assemblies of tau and RNA-binding proteins (RBPs), specifically Musashi (MSI), are implicated in Alzheimer's disease (AD).
• The precise role of MSI and tau interaction in their aggregation and its consequences in neurodegenerative diseases remain unclear.

Purpose of the Study:

• To investigate the expression and cellular localization of MSI1 and MSI2 in brain tissues from AD, ALS, and FTD patients.
• To examine the interaction between MSI and tau in various mouse models, including wild-type, tau knock-out, and P301L tau models.

Main Methods:

• Immunohistochemistry and biochemical analyses of brain tissues from human patients and mouse models.
• Assessment of protein localization, complex formation, and cellular transport mechanisms.

Main Results:

• Aberrant interactions between MSI and tau in the nucleus drive the formation of pathologically relevant protein inclusions.
• Age-dependent extracellular deposition of tau/MSI complexes was observed.
• Tau and MSI interactions led to impaired nuclear-cytoplasmic transport, chromatin remodeling, and nuclear lamina formation.

Conclusions:

• MSI-tau interactions are mechanistically linked to the pathological accumulation of aggregates in neurodegenerative proteinopathies.
• These findings provide a potential basis for developing therapeutic interventions targeting MSI/tau aggregates.