PUBLICATION
Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics
- Authors
- Roussange, F., Gide, J., Tournois, J., Cailleret, M., Boland, A., Battail, C., Deleuze, J.F., Polvèche, H., Auboeuf, D., Brockmann, K., Kabashi, E., Marian, A., El Kassar, L., Blondel, S., Salachas, F., Bruneteau, G., Peschanski, M., Martinat, C., Baghdoyan, S.
- ID
- ZDB-PUB-260626-19
- Date
- 2026
- Source
- Stem Cell Reports : 102977 (Journal)
- Registered Authors
- Keywords
- SQSTM1, amyotrophic lateral sclerosis, autophagy, drug repositioning, gene expression mapping, motor neurons, personalized therapies, pluripotent stem cells, repurposing
- MeSH Terms
- none
- PubMed
- 42349423 Full text @ Stem Cell Reports
Citation
Roussange, F., Gide, J., Tournois, J., Cailleret, M., Boland, A., Battail, C., Deleuze, J.F., Polvèche, H., Auboeuf, D., Brockmann, K., Kabashi, E., Marian, A., El Kassar, L., Blondel, S., Salachas, F., Bruneteau, G., Peschanski, M., Martinat, C., Baghdoyan, S. (2026) Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics. Stem Cell Reports. :102977.
Abstract
The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific genetic diseases. To remedy this, an alternative approach of reverse phenotypic mapping was tested: Compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping