CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model.
Jiaxi YuTongling LiufuYilei ZhengJin XuLingchao MengWei ZhangYun YuanDaojun HongNicolas Charlet-BerguerandZhaoxia WangJianwen DengPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- single cell
- rna seq
- high throughput
- binding protein
- oxidative stress
- multiple sclerosis
- cell therapy
- spinal cord injury
- cell death
- electron microscopy
- cell proliferation
- high resolution
- stem cells
- amino acid
- transcription factor
- gene expression
- case report
- mesenchymal stem cells
- dna methylation
- bone marrow
- subarachnoid hemorrhage
- protein kinase