Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: the polyG diseases.

Fiche publication

Date publication

avril 2021

Journal

Neuron

Auteurs

Membres identifiés du Cancéropôle Est :
Dr NEGRONI Luc , Dr CHARLET BERGUERAND Nicolas , Dr OULAD-ABDELGHANI Mustapha , Mr MORLET Bastien , Mr RUFFENACH Frank , Mme KOEBEL Pascale

Tous les auteurs :
Boivin M, Deng J, Pfister V, Grandgirard E, Oulad-Abdelghani M, Morlet B, Ruffenach F, Negroni L, Koebel P, Jacob H, Riet F, Dijkstra AA, McFadden K, Clayton WA, Hong D, Miyahara H, Iwasaki Y, Sone J, Wang Z, Charlet-Berguerand N

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33887199

Résumé

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.