Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations in the FUS gene are linked to severe forms of amyotrophic lateral sclerosis (ALS).
• Cytoplasmic accumulation of FUS protein is a key factor in FUS-related toxicity.
• The FUS gene autoregulates its own expression via a feedback loop involving its pre-mRNA.

Purpose of the Study:

• To investigate if introducing a wild-type FUS gene could counteract the effects of FUS mutations in a mouse model.
• To determine if FUS autoregulation can be leveraged as a therapeutic strategy for ALS.

Main Methods:

• Introduction of a wild-type FUS gene allele into mice expressing cytoplasmically mislocalized FUS (Fus^∆NLS).
• Assessment of survival, motor function, and FUS protein levels in treated mice.
• Analysis of endogenous mouse Fus mRNA, focusing on intron retention and mutant mRNA expression.

Main Results:

• Wild-type FUS expression completely rescued early lethality in homozygous Fus^∆NLS mice.
• It improved motor deficits and extended lifespan in heterozygous Fus^∆NLS mice.
• Wild-type FUS reactivated the autoregulatory loop, reducing cytoplasmic FUS levels and mutant mRNA expression.

Conclusions:

• Wild-type FUS expression effectively mitigates ALS-like phenotypes in mice by restoring autoregulation.
• Leveraging the FUS autoregulatory mechanism offers a potential therapeutic avenue for amyotrophic lateral sclerosis.
• This study provides proof of concept for using autoregulatory FUS gene therapy against neurodegenerative diseases.