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SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS.

Cell stem cell (2023-02-04)
Gabriel R Linares, Yichen Li, Wen-Hsuan Chang, Jasper Rubin-Sigler, Stacee Mendonca, Sarah Hong, Yunsun Eoh, Wenxuan Guo, Yi-Hsuan Huang, Jonathan Chang, Sharon Tu, Nomongo Dorjsuren, Manuel Santana, Shu-Ting Hung, Johnny Yu, Joscany Perez, Michael Chickering, Tze-Yuan Cheng, Chi-Chou Huang, Shih-Jong James Lee, Hao-Jen Deng, Kieu-Tram Bach, Kamden Gray, Vishvak Subramanyam, Jeffrey Rosenfeld, Samuel V Alworth, Hani Goodarzi, Justin K Ichida
RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.

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Ibuprofen, ≥98% (GC)
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Riluzole, solid
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Anastrozole, ≥98% (HPLC)
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Phenelzine sulfate salt
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Anti-SYF2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody