High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce...

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• The nematode Caenorhabditis elegans is a valuable model for neurodegenerative disease research due to its defined nervous system and genetics.
• Current drug screening methods for neurodegenerative diseases are limited by the need for high-throughput neuronal morphology analysis.
• A previously developed single-copy amyloid precursor protein (SC_APP) model in C. elegans recapitulates age- and cell-specific neurodegeneration.

Purpose of the Study:

• To explore novel chemical space for sigma 2 receptor (σ2R)/transmembrane protein 97 (TMEM97) ligands.
• To develop and implement an in vivo high-content screening (HCS) assay for identifying neuroprotective drug leads.
• To establish structure-activity relationships for σ2R/Tmem97 ligands.

Main Methods:

• Development of a C. elegans SC_APP-induced neurodegeneration model.
• Implementation of a high-throughput HCS assay utilizing microfluidic chips and automated imaging.
• Screening of a norbenzomorphan chemical library for neuroprotective compounds.

Main Results:

• Discovery of norbenzomorphans that effectively reduce neurodegeneration in the C. elegans model.
• Identification of two specific norbenzomorphan compounds exhibiting significant neuroprotective activity across multiple doses.
• Validation of the HCS assay for identifying potential therapeutic agents.

Conclusions:

• Norbenzomorphans targeting σ2R/Tmem97 demonstrate significant neuroprotective effects in a C. elegans model.
• These findings suggest that σ2R/Tmem97-binding norbenzomorphans represent a promising new drug class for neurodegenerative diseases.
• The developed HCS assay is effective for large-scale screening of neuroprotective compounds.