ArticleBrain : a journal of neurology2024
Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.
Article in Brain : a journal of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Genome-wide association studies identify genetic determinants of synucleinopathy biomarkers.Research square · 2026Article
- Genome-wide association studies identify genetic determinants of synucleinopathy biomarkers.medRxiv : the preprint server for health sciences · 2025Article
- An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.Science advances · 2025Article
- Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes.Molecular therapy. Nucleic acids · 2025Article
- Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.The Lancet. Neurology · 2025Review
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- The potential link between the development of Alzheimer's disease and osteoporosis.Biogerontology · 2025Review
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- FUS and METTL3 collaborate to regulate RNA maturation, preventing unfolded protein response and promoting gastric cancer progression.Clinical and experimental medicine · 2024Article
- APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease.Brain : a journal of neurology · 2024Article
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Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.
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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.