biostudies-literatureYu JNatural Science Foundation of Jiangxi ProvinceDouble thousand talents program of Jiangxi provinceCapitals Funds for Health Improvement and ResearchNational Natural Science Foundation of Chinae2208649119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9565157biostudies-literatureUnknown119(41)Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of the <i>NOTCH2NLC</i> gene. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models, albeit through an unknown mechanism. Here, we established a transgenic <i>Drosophila</i> model expressing uN2CpolyG in multiple systems, which resulted in progressive neuronal cell loss, locomotor deficiency, and shortened lifespan. Interestingly, electron microscopy revealed mitochondrial swelling both in transgenic flies and in muscle biopsies of individuals with NIID. Immunofluorescence and immunoelectron microscopy showed colocalization of uN2CpolyG witProceedings of the National Academy of Sciences of the United States of AmericaCGG repeat expansion in <i>NOTCH2NLC</i> causes mitochondrial dysfunction and progressive neurodegeneration in <i>Drosophila</i> model.PMC95651578146019920202BAB20602981571219U20A20356821602522022-4-4071682171846jxsq201910102182071409Zhang WZheng YCharlet-Berguerand NHong DDeng JMeng LYu JLiufu TWang ZXu JYuan YfalseCGG repeat expansion in <i>NOTCH2NLC</i> causes mitochondrial dysfunction and progressive neurodegeneration in <i>Drosophila</i> model.Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of the <i>NOTCH2NLC</i> gene. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models, albeit through an unknown mechanism. Here, we established a transgenic <i>Drosophila</i> model expressing uN2CpolyG in multiple systems, which resulted in progressive neuronal cell loss, locomotor deficiency, and shortened lifespan. Interestingly, electron microscopy revealed mitochondrial swelling both in transgenic flies and in muscle biopsies of individuals with NIID. Immunofluorescence and immunoelectron microscopy showed colocalization of uN2CpolyG wit2022-01-01T00:00:00Z2022 Oct2026-05-10T06:55:04.869Z2025-04-07T03:20:52.858ZS-EPMC95651573619123010.1073/pnas.2208649119