ArticleActa neuropathologica communications2024
Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.
Article in Acta neuropathologica communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.Neural regeneration research · 2026Article
- Review
- Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-frontotemporal dementia.Acta neuropathologica · 2026Article
- Genetic frontotemporal degeneration across the lifespan? A critical appraisal of the neurodevelopmental hypothesis.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.Journal of neurochemistry · 2026Review
- Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.Genes · 2026Review
- PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids.Brain : a journal of neurology · 2026Article
- Modeling ALS in a dish: how organoids are transforming research.Frontiers in medicine · 2026Review
- Are neurodegenerative diseases late-onset neurodevelopmental disorders? Tracing the developmental origins of neuronal vulnerability.Frontiers in neuroscience · 2026Review
- Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.Frontiers in neuroscience · 2026Review
- Single-cell sequencing and organoids: applications in organ development and disease.Molecular biomedicine · 2025Review
- Cellular Characterization and Neural Electrophysiology in Cerebral Organoid Models of Neurological Disorders.Aging and disease · 2025Review
- Deciphering brain organoid heterogeneity by identifying key quality determinants.Communications biology · 2025Article
- A Comparative Analysis of Grip Strength Evaluation Methods in a Large Cohort of Aged Mice.Journal of cachexia, sarcopenia and muscle · 2025Article
- The emergence of electrical activity in human brain organoids.Stem cell reports · 2025Review
- From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine.International journal of molecular sciences · 2025Review
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Authors and funding
21 authors.
Funding
Abstract
A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.
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