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

• DOI: 10.1016/j.neuron.2021.03.038
• Publication Date: 2021-04-21T17:37:20Z
• Authors: Manon Boivin; Jianwen Deng; Véronique Pfister; Erwan Grandgirard; Mustapha Oulad-Ab...; Bastien Morlet; Frank Ruffenach; Luc Negroni; Pascale Koebel; Hugues Jacob; Fabrice Riet; Anke A. Dijkstra; Kathryn McFadden; Wiley A. Clayton; Daojun Hong; Hiroaki Miyahara; Yasushi Iwasaki; Jun Sone; Zhaoxia Wang; Nicolas Charlet-B...
• Keywords: Cell Nucleus; Male; Cell Death; [SDV]Life Sciences [q-bio]; Intranuclear Inclusion Bodies; neurodegeneration; Neurodegenerative Diseases; 3. Good health; Mice, Inbred C57BL; Mice; Open Reading Frames; polyglycine; HEK293 Cells; genetic diseases; RAN translation; Report; trinucleotide repeat disorder; Animals; Humans; Peptides; Trinucleotide Repeat Expansion; polyG; Cells, Cultured; Locomotion

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