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Published on: October 28, 2019
Rewiring ALS by modulating the autophagy receptor SQSTM1
Laetitia Aubry1, Viktor I Korolchuk2, Sovan Sarkar3
1CECS/AFM, I-STEM, Corbeil-Essonnes 91100, France; INSERM/UEPS, UMR 861, Paris-Saclay University, I-STEM, Corbeil-Essonnes 91100, France.
Stem Cell Reports
|June 25, 2026
Summary
Reverse phenotypic mapping aids drug discovery for genetic disorders. This method identified prazosin, a drug that improves motor neuron and zebrafish models of amyotrophic lateral sclerosis by increasing SQSTM1 expression.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Identifying disease-relevant phenotypes for drug screening in genetic disorders remains challenging.
- Current methods often struggle to link specific genetic mutations to observable disease characteristics.
Purpose of the Study:
- To explore reverse phenotypic mapping as a strategy to discover therapeutic gene expression signatures.
- To identify potential drug candidates for amyotrophic lateral sclerosis (ALS) associated with SQSTM1 haploinsufficiency.
Main Methods:
- Employed reverse phenotypic mapping to uncover gene expression patterns.
- Utilized induced pluripotent stem cell (iPSC)-derived motor neurons and a zebrafish model.
- Tested identified drug candidates for their efficacy in rescuing disease phenotypes.
Main Results:
- Successfully identified prazosin as a therapeutic agent through reverse phenotypic mapping.
- Demonstrated that prazosin increases sequestosome-1 (SQSTM1) expression.
- Showcased the rescue of disease phenotypes in both iPSC-derived motor neurons and a zebrafish model of ALS.
Conclusions:
- Reverse phenotypic mapping is a viable approach for uncovering therapeutic gene expression signatures.
- Prazosin shows promise in treating ALS linked to SQSTM1 haploinsufficiency by modulating SQSTM1 levels.
- This strategy offers a novel avenue for drug discovery in genetic neurological disorders.
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