ArticleStem cell reports2020
Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.
Article in Stem cell reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 65 citations in OpenAlex.
- Intrathecal (GActa neuropathologica communications · 2026Article
- Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.bioRxiv : the preprint server for biology · 2026Article
- Article
- Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.Journal of neuroinflammation · 2025Article
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.Frontiers in cellular neuroscience · 2025Article
- CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.Frontiers in neurology · 2025Review
- Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.Acta neuropathologica communications · 2024Article
- Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.Stem cell reports · 2024Article
- Neural Differentiation and spinal cord organoid generation from induced pluripotent stem cells (iPSCs) for ALS modelling and inflammatory screening.Molecular neurobiology · 2024Article
- Reversal ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.Acta neuropathologica · 2024Article
- iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons.Cell reports · 2023Article
- A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons.Acta neuropathologica communications · 2023Article
- Mitochondrial Dysfunction in Repeat Expansion Diseases.Antioxidants (Basel, Switzerland) · 2023Review
- Loss of PML nuclear bodies in familial amyotrophic lateral sclerosis-frontotemporal dementia.Cell death discovery · 2023Article
- Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor neurons impair axonal initial segment integrity.Cellular and molecular life sciences : CMLS · 2023Article
- Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.Nature communications · 2023Article
- Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.Frontiers in cellular neuroscience · 2023Article
Corrections and comments
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Authors and funding
19 authors at 8 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.
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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.