Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS...

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• FUS protein aggregates in the cytoplasm, a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• The role of FUS-RNA interactions in phase separation and the impact of ALS-linked mutations remain unclear.

Purpose of the Study:

• To investigate how FUS-RNA interactions influence phase separation.
• To determine if ALS-linked mutations affect FUS phase behavior.
• To elucidate the mechanisms underlying FUS-related neurodegenerative diseases.

Main Methods:

• Studied wild-type and mutant FUS protein interactions with single-stranded RNA.
• Analyzed FUS condensate dynamics and formation.
• Investigated the effect of Karyopherin-β2 on FUS behavior.

Main Results:

• Wild-type FUS binds RNA stoichiometrically; multimers form dynamic, fluid condensates.
• Arginine mutations cause altered conformation, static RNA binding, and large condensates.
• Glycine mutations lead to rapid loss of condensate fluidity.
• Karyopherin-β2 reversed mutant FUS defects, restoring wild-type behavior.

Conclusions:

• FUS-RNA interactions are crucial for proper phase separation and condensate dynamics.
• ALS-linked FUS mutations disrupt these interactions, leading to distinct pathogenic pathways.
• Karyopherin-β2 shows potential in mitigating FUS mutant defects.