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

Neuron. 2021 Jun 2;109(11):1825-1835.e5. doi: 10.1016/j.neuron.2021.03.038. | PubMed

Manon Boivin¹, Jianwen Deng², Véronique Pfister¹, Erwan Grandgirard¹, Mustapha Oulad-Abdelghani¹, Bastien Morlet¹, Frank Ruffenach¹, Luc Negroni¹, Pascale Koebel¹, Hugues Jacob¹, Fabrice Riet¹, Anke A Dijkstra³, Kathryn McFadden⁴, Wiley A Clayton⁵, Daojun Hong⁶, Hiroaki Miyahara⁷, Yasushi Iwasaki⁷, Jun Sone⁸, Zhaoxia Wang², Nicolas Charlet-Berguerand⁹

1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France.
2. Department of Neurology, Peking University First Hospital, Beijing 100034, China.
3. Department of Pathology, Amsterdam University Medical Centre, Amsterdam Neuroscience, VUmc, Amsterdam, the Netherlands.
4. Department of Pathology, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
5. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
6. Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China.
7. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.
8. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan; Department of Neurology, Suzuka National Hospital, Suzuka 513-8501, Japan.
9. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France. Electronic address: ncharlet@igbmc.fr.

Abstract

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.

*Presented By Manon Boivin