Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy

Research output: Contribution to journalResearch articleContributedpeer-review


Aging is associated with the disruption of protein homeostasis and causally contributes to multiple diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons against age-dependent diseases such as ALS is to de-repress autophagy. BECN1 is a master regulator of autophagy; however, is repressed by BCL2 via a BH3 domain-mediated interaction. We used an induced pluripotent stem cell model of ALS caused by mutant FUS to identify a small molecule BH3 mimetic that disrupts the BECN1-BCL2 interaction. We identified obatoclax as a brain-penetrant drug candidate that rescued neurons at nanomolar concentrations by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration. Proteomics data suggest that obatoclax protects neurons via multiple mechanisms. Thus, obatoclax is a candidate for repurposing as a possible ALS therapeutic and, potentially, for other age-associated disorders linked to defects in protein homeostasis.</jats:p>


Original languageEnglish
Article number2247
Number of pages17
Volume12 (2023)
Issue number18
Publication statusPublished - 11 Sept 2023

External IDs

ORCID /0000-0002-4482-6010/work/142660215
unpaywall 10.3390/cells12182247
Scopus 85172808022
PubMed 37759469



  • Humans, Amyotrophic Lateral Sclerosis/metabolism, Motor Neurons/metabolism, Induced Pluripotent Stem Cells/metabolism, Mutation, Autophagy/physiology, Phenotype, Proto-Oncogene Proteins c-bcl-2/metabolism, RNA-Binding Protein FUS/genetics

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