M⁶A reduction relieves FUS-associated ALS granules

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) involves motoneuron degeneration and the formation of cytoplasmic inclusions from mutant proteins like FUS.
• RNA N6-methyladenosine (m⁶A) modification plays a role in cellular processes, but its specific involvement in ALS pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of m⁶A content in the formation and dissolution of FUS-induced inclusions in ALS.
• To explore the potential of targeting m⁶A pathways for therapeutic intervention in ALS.

Main Methods:

• Utilized neuronal cells and induced pluripotent stem cell (iPSC)-derived motoneurons expressing mutant FUS.
• Manipulated m⁶A RNA content and analyzed the number and dissolution rate of FUS inclusions.
• Examined the transcriptome of stress granules in ALS conditions.
• Treated patient-derived fibroblasts with METTL3 inhibitor STM-2457.

Main Results:

• Diminishing m⁶A content significantly reduced the number and accelerated the dissolution of FUS inclusions in neuronal cells and iPSC-derived motoneurons.
• ALS conditions altered the transcriptome of stress granules, which normalized after m⁶A downregulation.
• Cells expressing mutant FUS exhibited higher m⁶A levels, indicating a potential link between m⁶A homeostasis and aggregate formation.
• Treatment with METTL3 inhibitor STM-2457 reduced FUS inclusions in patient-derived fibroblasts.

Conclusions:

• Reduced m⁶A levels effectively counteract pathological FUS aggregate formation in ALS cellular models.
• m⁶A homeostasis is implicated in ALS pathogenesis, suggesting it as a potential therapeutic target.
• METTL3 inhibition shows promise for reducing FUS inclusions, offering a potential therapeutic avenue for ALS treatment.