A noncoding RNA modulator potentiates phenylalanine metabolism in mice

Area of Science:

• Genetics
• Molecular Biology
• Metabolic Disorders

Background:

• The role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders remains largely unexplored.
• Phenylketonuria (PKU) is a genetic disorder characterized by the inability to metabolize phenylalanine (Phe).

Purpose of the Study:

• To investigate the functional role of lncRNAs in PKU.
• To explore lncRNAs as potential therapeutic targets for PKU.

Main Methods:

• Studied the association of mouse lncRNA Pair and human HULC with phenylalanine hydroxylase (PAH).
• Utilized Pair-knockout mice and human induced pluripotent stem cell-differentiated hepatocytes for experiments.
• Developed and tested GalNAc-tagged HULC lncRNA mimics as a therapeutic strategy.

Main Results:

• Pair-knockout mice models recapitulated key features of human PKU, including elevated Phe levels and neurological symptoms.
• HULC depletion reduced PAH enzymatic activity by affecting substrate and cofactor interactions.
• Treatment with GalNAc-HULC mimics effectively lowered Phe levels and improved Phe tolerance in mouse models.

Conclusions:

• lncRNAs, specifically HULC, play a significant role in regulating PAH activity and Phe metabolism.
• HULC modulates PAH enzymatic function by influencing substrate and cofactor binding.
• GalNAc-conjugated HULC mimics represent a viable therapeutic approach for PKU by restoring lncRNA function in the liver.