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

Area of Science:

• Neuroscience
• Molecular Biology
• Gerontology

Background:

• Aging disrupts protein homeostasis, contributing to diseases like amyotrophic lateral sclerosis (ALS).
• Autophagy, a cellular cleaning process, can be repressed by BCL2 interacting with BECN1, hindering protein homeostasis.
• Restoring autophagy is a therapeutic strategy for neurodegenerative diseases.

Purpose of the Study:

• To identify a small molecule that disrupts the BECN1-BCL2 interaction, thereby de-repressing autophagy.
• To evaluate the therapeutic potential of such a molecule in an induced pluripotent stem cell (iPSC) model of ALS.

Main Methods:

• Utilized an iPSC model derived from ALS patients with mutant FUS.
• Screened for small molecule BH3 mimetics that disrupt the BECN1-BCL2 interaction.
• Assessed obatoclax's neuroprotective effects, including its impact on cytoplasmic FUS levels and protein homeostasis.

Main Results:

• Identified obatoclax, a brain-penetrant drug, that disrupts the BECN1-BCL2 interaction.
• Obatoclax rescued neurons at nanomolar concentrations in the ALS iPSC model.
• Demonstrated that obatoclax reduces cytoplasmic FUS levels, restores protein homeostasis, and reduces neuronal degeneration.

Conclusions:

• Obatoclax shows promise as a therapeutic candidate for ALS by restoring protein homeostasis.
• The drug's ability to protect neurons suggests potential applications for other age-associated disorders linked to protein homeostasis defects.