Arginine methylation of RNA-binding proteins is impaired in Huntington's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene (HTT).
• Cellular pathogenesis mechanisms in HD are unclear, but abnormal huntingtin protein (HTT) interactions are implicated.
• Protein arginine methylation, mediated by PRMT enzymes, is a crucial post-translational modification with known roles in neurodegeneration.

Purpose of the Study:

• To investigate the role of huntingtin protein (HTT) interactions with protein arginine methyl-transferase (PRMT) enzymes in Huntington's disease (HD).
• To explore how these interactions affect arginine methylation and cellular functions, particularly RNA processing, in HD.
• To identify potential therapeutic targets for HD based on arginine methylation pathways.

Main Methods:

• In vitro assays to assess HTT facilitation of PRMT activity and arginine methylation complex formation.
• Quantitative proteome analysis of striatal precursor neurons from HD models.
• Identification and characterization of proteins interacting with HTT and affected by altered arginine methylation in HD cells.

Main Results:

• Normal HTT facilitates PRMT activity, while mutant HTT disrupts these interactions and arginine methylation in HD neurons.
• Proteome analysis revealed significantly altered arginine methylation in HD, particularly in RNA-binding proteins.
• Several RNA-binding proteins with reduced arginine methylation interact with HTT and show impaired RNA processing and localization in HD cells.

Conclusions:

• Huntingtin protein (HTT) directly interacts with methyl-transferase enzymes, modulating their activity and impacting global arginine methylation in HD.
• Disrupted arginine methylation and abnormal HTT interactions contribute to RNA processing defects in HD.
• Targeting arginine methylation presents a potential therapeutic strategy for Huntington's disease.