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Obatoclax rescues FUS-ALS phenotypes in iPSC-derived neurons by inducing autophagy

ABSTRACT: Disruption of protein homeostasis plays an essential role in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons is to de-repress autophagy by disrupting the inhibitory BECN1/BCL2 complex, which has been shown to improve healthspan and lifespan in mice. We screened small molecule BH3 mimetics using an induced pluripotent stem cell (iPSC)-based model of ALS with a FUS mutation and identified obatoclax rescued neurons at by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Marc Gentzel

LAB HEAD: Prof. Dr. Jared Sterneckert

PROVIDER: PXD042427 | Pride | 2023-10-16

REPOSITORIES: Pride

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Overriding FUS autoregulation triggers gain-of-toxic dysfunctions in autophagy-lysosome axis and RNA metabolism

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