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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Abstract

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>

Details

OriginalspracheEnglisch
Aufsatznummer2247
FachzeitschriftCells
Jahrgang12
Ausgabenummer18
PublikationsstatusVeröffentlicht - 11 Sept. 2023
Peer-Review-StatusJa

Externe IDs

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

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