FUS is an N1- and N6-methyladenosine-binding protein.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Nucleotide repeat expansions are linked to neurological disorders.
• Mutations and overexpression of fused in sarcoma (FUS) protein cause amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Purpose of the Study:

• To investigate the role of RNA methylation in FUS protein interactions and cellular localization.
• To explore the potential of targeting FUS-RNA interactions for therapeutic interventions in FUS proteinopathies.

Main Methods:

• Investigated FUS protein binding to methylated RNA (m1A and m6A) using cell models (SH-SY5Y cells).
• Assessed FUS protein co-localization with CAG repeat RNA in the cytosol.
• Utilized genetic depletion and pharmacological inhibition of RNA methylation enzymes (METTL3, TRMT61A, ALKBH3, FTO) to study FUS localization.
• Measured FUS protein dynamics using binding to methylated RNA.

Main Results:

• FUS protein binds to methylated adenosines in CAG repeat expansion RNA.
• This binding leads to FUS protein's cytoplasmic redistribution and co-localization with CAG repeat RNA.
• Depletion or inhibition of RNA methylation enzymes, or overexpression of demethylases, reduced FUS co-localization.
• Binding to methylated RNA decreases FUS protein mobility in cells.

Conclusions:

• m1A and m6A modifications critically enhance FUS-RNA interactions, causing aberrant subcellular distribution and reduced protein mobility.
• This reveals a novel mechanism in neurodegenerative diseases associated with FUS overexpression.
• Targeting FUS-methylated adenosine interactions presents a potential therapeutic strategy for FUS proteinopathy.