Cytoplasmic granule formation by FUS-R495X is attributable to arginine methylation in all Gly-rich, RGG1 and RGG2...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in the fused in sarcoma (FUS) gene are linked to amyotrophic lateral sclerosis (ALS).
• FUS protein's ability to form cytoplasmic granules is implicated in ALS pathogenesis, but the underlying mechanisms are not fully understood.
• An ALS-linked FUS mutant, R495X, exhibits cytoplasmic localization and granule formation in neurons.

Purpose of the Study:

• To elucidate the molecular mechanisms governing the cytoplasmic granule formation of the ALS-linked FUS mutant R495X.
• To investigate the role of specific domains and arginine methylation in R495X-induced granule formation.

Main Methods:

• Utilized domain deletion constructs of the R495X FUS mutant to assess the impact on granule formation.
• Examined the effect of an arginine methylation inhibitor on R495X granule formation in neurons.
• Investigated the influence of co-expressing arginine N-methyltransferase 8 (PRMT8) on R495X-induced granule formation.

Main Results:

• Deletion of the Gly-rich, RGG1, or RGG2 domains of R495X significantly suppressed cytoplasmic granule formation.
• Inhibition of arginine methylation reduced the number of neurons exhibiting R495X granules.
• Enhanced methylation via PRMT8 co-expression increased the formation of R495X granules.

Conclusions:

• Cytoplasmic granule formation by the R495X FUS mutant is dependent on arginine methylation within its Gly-rich, RGG1, and RGG2 domains.
• These findings provide critical insights into the molecular basis of FUS-related ALS pathogenesis.
• Targeting arginine methylation may represent a potential therapeutic strategy for FUS-associated neurodegenerative diseases.