Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model.

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss.
• Proteinopathies, involving misfolded proteins, are implicated in ALS pathogenesis and activate the heat shock stress response (HSR).

Purpose of the Study:

• To pinpoint the timing, mechanism, and neuronal cell types initiating ALS pathophysiology.
• To utilize a transgenic mutant SOD1 zebrafish model to investigate disease onset.
• To screen for neuroprotective drugs that mitigate early disease processes.

Main Methods:

• Employed a transgenic zebrafish model expressing a fluorescent hsp70-DsRed reporter to monitor neuronal stress via HSR.
• Quantified functional changes in neurons and muscles throughout disease progression.
• Assessed spontaneous currents in spinal motor neurons and neuromuscular junction (NMJ) morphology.

Main Results:

• Heat shock stress response (HSR) was first detected in glycinergic interneurons at 24 hours postfertilization (hpf).
• A significant decrease in spontaneous glycinergic currents to motor neurons occurred by 96 hpf.
• Adult symptomatic fish showed increased motor neuron stress and NMJ denervation; riluzole and apomorphine reduced early neuronal stress.

Conclusions:

• ALS pathophysiology in this model initiates with neuronal stress in inhibitory interneurons due to mutant SOD1.
• Reduced inhibitory input to motor neurons may drive subsequent motor neuron stress and NMJ dysfunction.
• Riluzole demonstrates a novel mechanism of action by modulating interneuron stress in ALS.