PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is caused by CAG repeat expansion in the Huntingtin (HTT) gene, leading to toxic polyglutamine-expanded HTT protein.
• Current therapeutic strategies for HD focus on reducing HTT protein levels, with splice modulators showing promise.
• Understanding HTT gene regulation is crucial for developing effective HD treatments.

Purpose of the Study:

• To identify novel regulators of HTT mRNA splicing and alternative polyadenylation.
• To investigate the role of PRMT5 in HTT gene expression.
• To explore the therapeutic potential of targeting PRMT5 for Huntington's disease.

Main Methods:

• Investigated PRMT5 as a regulator of HTT splicing and alternative polyadenylation.
• Analyzed the impact of PRMT5 inhibition on HTT mRNA processing, including intron splicing and polyadenylation.
• Examined HTT transcript levels during neuronal differentiation and in response to PRMT5 inhibition in glioblastoma stem cells.

Main Results:

• PRMT5 was identified as a novel regulator of HTT mRNA splicing and alternative polyadenylation.
• PRMT5 inhibition disrupted HTT intron 9 and 10 splicing, activating intronic polyadenylation sites and promoting premature mRNA termination.
• Truncated HTT transcripts increased during neuronal differentiation, correlating with decreased PRMT5 expression; PRMT5 inhibition induced neuronal differentiation in glioblastoma stem cells.

Conclusions:

• PRMT5 plays a significant role in modulating HTT mRNA expression through regulation of intronic polyadenylation and premature termination.
• PRMT5 inhibition offers a potential therapeutic strategy for Huntington's disease by reducing pathogenic HTT protein levels.
• PRMT5-mediated regulation of HTT mRNA is important during neuronal differentiation.