FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The RNA/DNA-binding protein FUS is implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).
• The precise disease mechanisms involving FUS remain largely undetermined.
• Understanding FUS's role in neuronal function is crucial for neurodegenerative disease research.

Purpose of the Study:

• To investigate the intrinsic functions of FUS in synaptic physiology.
• To elucidate the molecular mechanisms by which FUS influences neuronal function and behavior.
• To evaluate the role of FUS in the context of FTLD-like phenotypes.

Main Methods:

• FUS knockdown in cultured neurons and in vivo models.
• Analysis of GluA1 (AMPA receptor subunit) expression and localization.
• Electrophysiological recordings to measure miniature EPSC amplitude.
• Assessment of dendritic spine maturation and behavioral testing in animal models.

Main Results:

• FUS depletion led to downregulation of the AMPA receptor subunit GluA1.
• FUS was found to bind GluA1 mRNA, regulating its stability via poly (A) tail maintenance.
• Reduced GluA1 levels impaired synaptic transmission (miniature EPSC amplitude).
• FUS knockdown resulted in impaired dendritic spine maturation and FTLD-like behaviors (hyperactivity, disinhibition, social deficits).

Conclusions:

• FUS plays a critical role in maintaining GluA1 mRNA stability and regulating post-synaptic function.
• Dysregulation of FUS impacts neuronal structure and synaptic activity, contributing to FTLD-like behaviors.
• Targeting FUS-mediated regulation of GluA1 offers potential therapeutic avenues for FTLD.