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

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 11; pp. 1825 - 1835.e5
• Main Authors: Boivin, Manon, Deng, Jianwen, Pfister, Véronique, Grandgirard, Erwan, Oulad-Abdelghani, Mustapha, Morlet, Bastien, Ruffenach, Frank, Negroni, Luc, Koebel, Pascale, Jacob, Hugues, Riet, Fabrice, Dijkstra, Anke A., McFadden, Kathryn, Clayton, Wiley A., Hong, Daojun, Miyahara, Hiroaki, Iwasaki, Yasushi, Sone, Jun, Wang, Zhaoxia, Charlet-Berguerand, Nicolas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.06.2021; Elsevier Limited; Elsevier; Cell Press
• Subjects: 5' Untranslated Regions; Amino acids; Animal models; Antibodies; Ataxia; Cell culture; Cell death; Cloning; Cytomegalovirus; Dementia; Disease; genetic diseases; Genetic disorders; Genomes; Inclusion bodies; Life Sciences; Mass spectrometry; Neurodegeneration; Neurodegenerative diseases; polyG; polyglycine; Proteins; RAN translation; Scientific imaging; Translation; trinucleotide repeat disorder; genetic diseases; neurodegeneration; RAN translation; trinucleotide repeat disorder; polyG; polyglycine
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.03.038

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. [Display omitted] •NIID is a neurodegenerative disease caused by expansion of GGC repeats in NOTCH2NLC•These GGC repeats are translated into a polyglycine (polyG) protein•The polyG protein is toxic and forms intranuclear inclusions in cells and animals•Similarities between FXTAS and NIID define a new set of disorders: polyG diseases The neurodegenerative disease NIID is caused by an expansion of GGC repeats in NOTCH2NLC. Boivin et al. found that these repeats are translated into a toxic polyglycine (polyG) protein that forms intranuclear inclusions. An identical mechanism exists in FXTAS, unveiling a novel group of genetic pathologies, the polyG diseases.