A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells

Area of Science:

• Neuroscience
• Stem Cell Biology
• Genetics

Background:

• Developing therapeutics for complex neurodegenerative diseases like sporadic amyotrophic lateral sclerosis (ALS) is challenging due to the lack of relevant disease models.
• Induced pluripotent stem cells (iPSC) offer a promising avenue for creating patient-specific cellular models.

Purpose of the Study:

• To generate patient-derived iPSC and differentiate them into motor neurons to model sporadic ALS.
• To utilize these cellular models for high-content chemical screening to identify potential drug candidates.

Main Methods:

• Fibroblasts from a cohort of healthy controls and sporadic ALS patients were reprogrammed into iPSC.
• iPSC were differentiated into motor neurons, including lower and upper motor neuron-like cells.
• A high-content chemical screen was performed using TDP-43 aggregation as a disease endpoint.

Main Results:

• Motor neurons derived from three sporadic ALS patients exhibited de novo TDP-43 aggregation.
• The observed TDP-43 aggregates recapitulated pathology found in postmortem patient tissue.
• The screen identified FDA-approved small molecule modulators, including Digoxin, as effective.

Conclusions:

• Patient-derived iPSC provide a feasible platform for modeling sporadic ALS and its associated TDP-43 pathology.
• This iPSC-based model is effective for drug screening, demonstrating potential for therapeutic discovery in ALS.