CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model - Archive ouverte HAL
Article Dans Une Revue Proceedings of the National Academy of Sciences Année : 2022

CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model

Jiaxi Yu
  • Fonction : Auteur
Tongling Liufu
  • Fonction : Auteur
Yilei Zheng
  • Fonction : Auteur
Jin Xu
  • Fonction : Auteur
Lingchao Meng
  • Fonction : Auteur
Wei Zhang
  • Fonction : Auteur
Yun Yuan
  • Fonction : Auteur
Daojun Hong
  • Fonction : Auteur
Zhaoxia Wang
  • Fonction : Auteur
Jianwen Deng
  • Fonction : Auteur

Résumé

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 NOTCH2NLC 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 Drosophila 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 with mitochondria in cell and patient samples, while biochemical analysis revealed that uN2CpolyG interacted with a mitochondrial RNA binding protein, LRPPRC (leucine-rich pentatricopeptide repeat motif-containing protein). Furthermore, RNA sequencing (RNA-seq) analysis and functional assays showed down-regulated mitochondrial oxidative phosphorylation in uN2CpolyG-expressing flies and NIID muscle biopsies. Finally, idebenone treatment restored mitochondrial function and alleviated neurodegenerative phenotypes in transgenic flies. Overall, these results indicate that transgenic flies expressing uN2CpolyG recapitulate key features of NIID and that reversing mitochondrial dysfunction might provide a potential therapeutic approach for this disorder.
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Dates et versions

hal-04220480 , version 1 (27-09-2023)

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Jiaxi Yu, Tongling Liufu, Yilei Zheng, Jin Xu, Lingchao Meng, et al.. CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model. Proceedings of the National Academy of Sciences, 2022, 119 (41), ⟨10.1073/pnas.2208649119⟩. ⟨hal-04220480⟩
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