ArticlePLoS genetics2023
Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.
Article in PLoS genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 3 of them syntheses that pooled it.
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Who cites it
39 citing papers in PubMed, 3 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.Frontiers in molecular neuroscience · 2026Pooled it
- C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.Frontiers in molecular neuroscience · 2025Pooled it
- NADPH oxidases in immunometabolism and disease pathology: mechanistic networks, pollutant triggers, and therapeutic frontiers.Cellular & molecular immunology · 2026Review
- TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.Journal of neurochemistry · 2026Review
- Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.Nature genetics · 2026Article
- Review
- A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.PLoS biology · 2026Article
- Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism.Molecular psychiatry · 2026Article
- Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.bioRxiv : the preprint server for biology · 2026Article
- Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.Frontiers in neuroscience · 2026Review
- Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis.Brain communications · 2026Article
- The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins.bioRxiv : the preprint server for biology · 2025Article
- TDP-43: unveiling the hidden key to cellular fate decisions.Cell communication and signaling : CCS · 2025Review
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Review
- Human Brain Organoids Model Abnormal Prenatal Neural Development Induced by Thermal Stimulation.Cell proliferation · 2025Article
- Prion and "Prion-Like" Detection: From Conventional Methods to Microfluidics or Lab-on-Chip Platforms to Monitor Seeding and Spreading of Misfolded Proteins.Sub-cellular biochemistry · 2025Review
- Seed Amplification Assays as Powerful Tools for Detecting Peripheral Biomarkers in Prion-Like Diseases.Sub-cellular biochemistry · 2025Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.