Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory...

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease with unknown causes.
• Familial ALS is linked to mutations in genes like SOD1, TARDBP, and FUS.
• The FUS (P525L) mutation's impact on spinal neuron function is not fully understood.

Purpose of the Study:

• To investigate the functional effects of the FUS (P525L) mutation on human induced pluripotent stem cell (hiPSC)-derived spinal neurons.
• To determine how this mutation influences neuronal maturation and synaptic transmission.

Main Methods:

• Utilized hiPSCs to generate spinal neurons carrying the FUS (P525L) mutation.
• Performed electrophysiological recordings to assess neuronal function, including membrane potential, action potentials, and synaptic currents (GABA, glycine, glutamate).
• Quantified glycine receptor subunit expression using immunofluorescence assays.

Main Results:

• FUS (P525L) mutation delayed neuronal functional maturation, showing altered membrane potentials and reduced synaptic activity.
• Mutated neurons exhibited significantly reduced responses to inhibitory neurotransmitters GABA and glycine.
• A decrease in glycine receptor α1 subunit expression was observed in mutated neurons.

Conclusions:

• The FUS (P525L) mutation impairs hiPSC-derived spinal neuron maturation and function, particularly inhibitory signaling.
• This disruption in the excitatory/inhibitory balance may predispose neurons to excitotoxicity and neurodegeneration in ALS.
• Findings confirm the causative role of the FUS (P525L) mutation in observed neuronal deficits.