CAG repeat expansion in the Huntington's disease gene shapes linear and circular RNAs biogenesis

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alternative splicing (AS) alterations are noted in Huntington's disease (HD).
• The role of AS in early, pre-symptomatic HD stages remains unclear.

Purpose of the Study:

• To investigate the significance of AS in early, pre-symptomatic HD.
• To explore the impact of Htt CAG repeat length on AS and RNA production.

Main Methods:

• Utilized Htt CAG knock-in mouse models (in vitro and in vivo).
• Analyzed aberrant linear and circular RNA splicing patterns.
• Performed integrative transcriptomic analyses of micro-RNAs and RNA-binding proteins.

Main Results:

• Demonstrated a correlation between Htt CAG repeat length and increased aberrant linear AS in neural progenitors and striatum before symptom onset.
• Identified 36% of aberrant isoforms as non-functional, targeted for nonsense-mediated decay (NMD).
• Revealed a global impairment of back-splicing, leading to decreased circular RNA production.

Conclusions:

• Expanded Htt CAG repeats disrupt RNA splicing balance in neural cells.
• Altered expression of linear and circular RNAs may contribute to HD pathogenesis.
• Identified a network of micro-RNAs and RNA-binding proteins potentially influencing AS in HD.