Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation.

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Drug development faces challenges with inaccurate target identification.
• Phenotypic screens using patient-derived stem cells offer unbiased target validation and discovery.
• Neuronal hyperexcitability is a key pathological feature in amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To identify novel therapeutic targets for managing hyperexcitability in ALS.
• To validate existing targets by assessing their role in ALS motor neuron function.
• To demonstrate the utility of human disease cell-based phenotypic screens in neurological drug discovery.

Main Methods:

• A multi-step screening approach was employed using patient-derived motor neurons.
• High-content live cell imaging assessed neuronal excitability.
• A chemogenomic library of 2,899 compounds was screened against ALS motor neurons with the SOD1(A4V) mutation.

Main Results:

• 67 compounds were found to reduce hyperexcitability in ALS motor neurons without causing cytotoxicity.
• Bioinformatic analysis identified 13 targets modulating motor neuron excitability.
• Known ALS targets (AMPA receptors, Kv7.2/3 channels) and a novel target (D2 dopamine receptors) were validated.

Conclusions:

• Human disease cell-based phenotypic screens are powerful tools for identifying clinically relevant neurological targets.
• The study validated known ALS targets and discovered D2 dopamine receptors as novel modulators of motor neuron excitability.
• This approach holds promise for advancing drug development for neurodegenerative disorders like ALS.