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Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD
Astrid T van der Geest1, Channa E Jakobs1, Tijana Ljubikj1
1Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Acta Neuropathologica Communications
|September 17, 2024
Summary
A hexanucleotide repeat expansion (HRE) in C9ORF72 causes ALS/FTD. Patient-derived brain organoids reveal early molecular and synaptic changes, even in presymptomatic carriers, offering insights into disease onset.
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- The C9ORF72 hexanucleotide repeat expansion (HRE) is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Early structural and connectivity changes in the brain occur in C9-ALS/FTD before symptom onset, but these phenotypes are not fully understood.
Purpose of the Study:
- To investigate early molecular and cellular changes in the brain using induced pluripotent stem cell (iPSC)-derived cerebral organoids from C9-ALS/FTD patients and presymptomatic carriers.
- To understand the initial pathologies contributing to C9-ALS/FTD onset and inform therapeutic strategies.
Main Methods:
- Generation of iPSC-derived cerebral organoids from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE carriers, and controls.
- Utilized single-cell RNA sequencing, molecular and cellular analyses, and patch-clamp electrophysiology to assess organoid phenotypes.
Main Results:
- Cerebral organoids from C9-ALS/FTD patients exhibited all three C9-HRE molecular pathologies and developmental size alterations.
- Single-cell RNA sequencing revealed altered cell type abundance, including reduced deep layer cortical neurons and changes in neural progenitor distribution.
- Synapse structure and function were altered, and presymptomatic carriers showed C9-HRE molecular pathology, with varying downstream cellular defects.
Conclusions:
- Cerebral organoids model early C9-ALS/FTD pathologies, including molecular and synaptic alterations.
- Presymptomatic carriers display molecular pathology, indicating early disease processes.
- These findings highlight crucial initial pathologies in 3D human brain tissue relevant for understanding disease onset and developing therapies.
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