Reactive astrocytes in ALS display diminished intron retention

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Reactive astrocytes play a role in amyotrophic lateral sclerosis (ALS) pathogenesis.
• The molecular mechanisms governing astrocyte reactivity remain largely unknown.

Purpose of the Study:

• To investigate the role of intron retention (IR) in astrocyte reactive transformation.
• To elucidate the molecular mechanisms linking genetic mutations to astrocyte reactivity in ALS.

Main Methods:

• Analysis of intron retention in human-induced pluripotent stem cell (hiPSC)-derived astrocytes with ALS-causing mutations (VCP, SOD1, C9orf72).
• Comparison with public datasets of cytokine-stimulated astrocytes and in vivo astrocytes with TDP-43 deletion.
• Re-examination of translatome sequencing (TRAP-seq) data from a SOD1 mouse model.
• Nucleocytoplasmic fractionation, mRNA sequencing, and proteomics in VCP mutant astrocytes.

Main Results:

• Decreased intron retention (IR) is a common feature in astrocytes with ALS-associated mutations.
• Transcripts with reduced IR are linked to astrocyte reactivity pathways (cell adhesion, stress response, immune activation).
• Reduced IR correlates with enhanced nonsense-mediated decay and increased cytoplasmic expression of reactivity-related genes and proteins.

Conclusions:

• A molecular model for astrocyte reactive transformation is proposed, involving splicing, nuclear export, and translation of IR transcripts.
• Altered intron retention represents a key regulatory mechanism in astrocyte reactivity relevant to ALS.
• This study offers novel insights into the molecular basis of astrocyte dysfunction in neurodegenerative diseases like ALS.