A noncoding RNA modulator potentiates phenylalanine metabolism in mice.

Date publication

août 2021

Journal

Science (New York, N.Y.)

Auteurs

Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis , Dr NAMOUR Bernard

Tous les auteurs :
Li Y, Tan Z, Zhang Y, Zhang Z, Hu Q, Liang K, Jun Y, Ye Y, Li YC, Li C, Liao L, Xu J, Xing Z, Pan Y, Chatterjee SS, Nguyen TK, Hsiao H, Egranov SD, Putluri N, Coarfa C, Hawke DH, Gunaratne PH, Tsai KL, Han L, Hung MC, Calin GA, Namour F, Guéant JL, Muntau AC, Blau N, Sutton VR, Schiff M, Feillet F, Zhang S, Lin C, Yang L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/34353949

Résumé

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA and human associate with phenylalanine hydroxylase (PAH). -knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc- mimics reduced excessive Phe in and mice and improved the Phe tolerance of these mice.

Référence

Science. 2021 Aug 6;373(6555):662-673