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Updated: May 7, 2026
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Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases
Published on: June 28, 2019
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PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids
Tijana Ljubikj1, Mayte Z Mars1, Astrid T van der Geest1
1Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht 3584 CG, The Netherlands.
Brain : a Journal of Neurology
|September 18, 2025
Summary
Microglia function is impaired in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) caused by C9ORF72 repeat expansions. Restoring the transcription factor PU.1 can rescue these microglial defects, offering a potential therapeutic target for C9-ALS/FTD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with unknown mechanisms.
- The C9ORF72 hexanucleotide repeat expansion (C9-ALS/FTD) is the most common genetic cause.
- The role of microglia, the brain's immune cells, in C9-ALS/FTD is unclear, with conflicting reports on their activity.
Purpose of the Study:
- To investigate microglial function in a complex, three-dimensional model of C9-ALS/FTD.
- To identify molecular mechanisms underlying microglial dysfunction in C9-ALS/FTD.
Main Methods:
- Developed cerebral organoids from induced pluripotent stem cells (iPSCs) of C9-ALS/FTD patients and controls.
- Analyzed transcriptional changes and cellular complexity of organoid-derived microglia (oMGs).
- Performed live imaging to assess microglial phagocytosis and engulfment of neuronal components.
- Utilized viral overexpression to manipulate transcription factor activity (PU.1).
Main Results:
- C9-ALS/FTD organoid-derived microglia (C9-oMGs) exhibited reduced cellular complexity and altered gene expression in immune and phagocytic pathways.
- Inflammatory cue release from C9-ALS/FTD organoids was decreased, with reduced LAMP1 expression in C9-oMGs.
- C9-oMGs showed impaired phagocytosis of synaptic proteins.
- Transcriptomics identified a downregulated PU.1 regulon in C9-oMGs, and PU.1 re-expression rescued functional deficits.
Conclusions:
- Microglial function is reduced in a complex cellular environment relevant to C9-ALS/FTD.
- Downregulation of PU.1 contributes to microglial dysfunction in C9-ALS/FTD.
- PU.1 is a potential therapeutic target for restoring microglial function in C9-ALS/FTD.
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