Functional Characterisation of the Circular RNA, circHTT(2-6), in Huntington's Disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Trinucleotide repeat disorders are inherited neurodegenerative conditions caused by expanded DNA repeats.
• Huntington's disease (HD), a common trinucleotide repeat disorder, arises from CAG repeat expansion in the HTT gene.
• Non-coding RNAs are increasingly recognized for their roles in disease pathogenesis.

Purpose of the Study:

• To investigate the role of circular RNA (circRNA) derived from the HTT gene in Huntington's disease.
• To characterize the expression and function of circHTT(2-6), a specific circRNA from the HTT gene.

Main Methods:

• Quantification of circHTT(2-6) expression in human brain samples and cell lines.
• Overexpression of circHTT(2-6) in human cell lines (SH-SY5Y, HEK293).
• Assessment of cellular phenotypes, cell cycle, and HTT protein localization following circHTT(2-6) overexpression.

Main Results:

• circHTT(2-6) expression is significantly higher in the frontal cortex of HD patients and correlates with CAG repeat length.
• The mouse orthologue, mmu_circHTT(2-6), is enriched in the brain, particularly the striatum.
• Overexpression of circHTT(2-6) in cell lines reduced cell proliferation and nuclear size, and decreased nuclear localization of HTT protein.

Conclusions:

• circHTT(2-6) is a potential biomarker for Huntington's disease.
• circHTT(2-6) may play a direct role in the pathophysiology of Huntington's disease by affecting cellular processes and HTT protein localization.