Early pathogenesis of spinal and bulbar muscular atrophy uncovered by human iPSC-derived motor neurons highlights pathogenic neuropeptides as therapeutic targets
Onodera, K.; Riku, Y.; Shimojo, D.; Ota, A.; Rashid, M. I.; Okada, R.; Yamaguchi, S.; Yamada, S.; Hosokawa, Y.; Yoshida, M.; Iwasaki, Y.; Doyu, M.; Sobue, G.; Katsuno, M.; Okano, H.; Okada, Y.
Show abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by the expansion of the polyglutamine tract in the androgen receptor (AR). Motor neurons (MNs) derived from patient-specific induced pluripotent stem cells (iPSCs) robustl y recapitulated early SBMA phenotypes driven by endogenous mutant AR in the absence of testosterone (dihydrotestosterone) and detectable mutant AR aggregation. Notably, endoplasmic reticulum stress markedly exacerbated SBMA pathology. Cross-species integrative analyses of patient-derived neurons and spinal cords of transgenic mouse models revealed high expression of multiple disease-associated neuropeptides, including urotensin II (UTS2), in patient spinal MNs that was correlated with disease onset and progression in iPSC-derived MNs. Downstream signaling analyses of these neuropeptides revealed convergent molecular pathways whose pharmacological inhibition rescued cellular phenotypes. Together, these results establish a human disease model harboring endogenous mutant AR that closely reproduces early SBMA pathology and provides molecular leads for elucidating disease mechanisms and biomarkers and developing therapeutic targets.
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