TY - JOUR
T1 - NU-9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone
AU - Genç, Barış
AU - Gautam, Mukesh
AU - Helmold, Benjamin R.
AU - Koçak, Nuran
AU - Günay, Aksu
AU - Goshu, Gashaw M.
AU - Silverman, Richard B.
AU - Hande Ozdinler, P.
N1 - Funding Information:
This study was supported by A Long Swim Foundation (P.H.O), NIH-NIA Grant R01 AG061708 (P.H.O, R.B.S), NUCATS N.XT. Northwestern University (P.H.O., R.B.S.), and ALSA TREAT ALS Award (R.B.S.). Dr. Gautam is the Ellen McConnell Blakeman Fellow of A Long Swim Foundation. We thank the Estaban Bullrich Foundation for covering publication cost, and we thank Dr. Derya Ozyurt (Mathworks Inc.) and Kate Pauss for statistical analyses.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.
AB - Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.
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U2 - 10.1038/s41598-022-09332-4
DO - 10.1038/s41598-022-09332-4
M3 - Article
C2 - 35354901
AN - SCOPUS:85127270699
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 5383
ER -