Ligand-free mitochondria-localized mutant AR-induced cytotoxicity in spinal bulbar muscular atrophy

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...

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Published in:Brain (London, England : 1878) England : 1878), 2023-01, Vol.146 (1), p.278-294
Main Authors: Feng, Xia, Cheng, Xiu-Tang, Zheng, Pengli, Li, Yan, Hakim, Jill, Zhang, Shirley Q, Anderson, Stacie M, Linask, Kaari, Prestil, Ryan, Zou, Jizhong, Sheng, Zu-Hang, Blackstone, Craig
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Humans
Induced Pluripotent Stem Cells - metabolism
Mitochondria - metabolism
Muscular Atrophy
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - metabolism
Original
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
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Summary: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awac269