Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene.
• Altered gene expression and RNA processing are hallmarks of HD, but the underlying mechanisms are not fully understood.
• TDP-43 protein mislocalization and N6-methyladenosine (m6A) RNA modification are implicated in various neurological conditions.

Purpose of the Study:

• To investigate the roles of TDP-43 and METTL3 in regulating RNA processing, specifically exon skipping, in Huntington's disease.
• To explore the relationship between TDP-43, m6A modification, and aberrant gene splicing in HD models.

Main Methods:

• Analysis of TDP-43 localization and phosphorylation in HD mouse and human brain tissues.
• Investigation of TDP-43 binding to target RNAs in HD systems.
• Quantification of m6A RNA modification levels on differentially expressed and spliced genes in HD mouse brains.

Main Results:

• Disrupted nuclear localization and cytoplasmic accumulation of TDP-43 were observed in HD brains.
• TDP-43 binding to specific HD-associated RNAs was decreased.
• Reduced m6A RNA modification was found on aberrantly expressed RNAs in the HD mouse striatum, particularly near TDP-43 binding sites.

Conclusions:

• TDP-43 loss of function contributes to aberrant alternative splicing in Huntington's disease.
• Altered m6A RNA modification is a key mechanism involved in the RNA processing defects observed in HD.
• The interplay between TDP-43 and m6A modification represents a novel therapeutic target for HD.