Ligand-free mitochondria-localized mutant AR-induced cytotoxicity in spinal bulbar muscular atrophy
| العنوان: | Ligand-free mitochondria-localized mutant AR-induced cytotoxicity in spinal bulbar muscular atrophy |
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| المؤلفون: | Xia Feng, Xiu-Tang Cheng, Pengli Zheng, Yan Li, Jill Hakim, Shirley Q Zhang, Stacie M Anderson, Kaari Linask, Ryan Prestil, Jizhong Zou, Zu-Hang Sheng, Craig Blackstone |
| المصدر: | Brain |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Original Article, Neurology (clinical) |
| الوصف: | Spinal bulbar muscular atrophy (SBMA), the first identified CAG-repeat expansion disorder, is an X-linked neuromuscular disorder involving CAG-repeat-expansion mutations in the androgen receptor (AR) gene. We utilized CRISPR-Cas9 gene editing to engineer novel isogenic human induced pluripotent stem cell (hiPSC) models, consisting of isogenic AR knockout, control and disease lines expressing mutant AR with distinct repeat lengths, as well as control and disease lines expressing FLAG-tagged wild-type and mutant AR, respectively. Adapting a small-molecule cocktail-directed approach, we differentiate the isogenic hiPSC models into motor neuron-like cells with a highly enriched population to uncover cell-type-specific mechanisms underlying SBMA and to distinguish gain- from loss-of-function properties of mutant AR in disease motor neurons. We demonstrate that ligand-free mutant AR causes drastic mitochondrial dysfunction in neurites of differentiated disease motor neurons due to gain-of-function mechanisms and such cytotoxicity can be amplified upon ligand (androgens) treatment. We further show that aberrant interaction between ligand-free, mitochondria-localized mutant AR and F-ATP synthase is associated with compromised mitochondrial respiration and multiple other mitochondrial impairments. These findings counter the established notion that androgens are requisite for mutant AR-induced cytotoxicity in SBMA, reveal a compelling mechanistic link between ligand-free mutant AR, F-ATP synthase and mitochondrial dysfunction, and provide innovative insights into motor neuron-specific therapeutic interventions for SBMA. |
| تدمد: | 1460-2156 0006-8950 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f2ede913ee9f73cc9446bdfca7f89841 https://doi.org/10.1093/brain/awac269 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f2ede913ee9f73cc9446bdfca7f89841 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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