ArticleAnnals of clinical and translational neurology2015
Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation.
Article in Annals of clinical and translational neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
What it found
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Who cites it
43 citing papers in PubMed, 65 citations in OpenAlex.
- DUX4-induced HSATII RNA accumulation drives protein aggregation, impacting RNA processing pathways.The Journal of cell biology · 2026Article
- Facioscapulohumeral Dystrophy: Molecular Basis and Therapeutic Opportunities.Cold Spring Harbor perspectives in biology · 2025Review
- Systemic Pharmacotherapeutic Treatment of the ACTA1-MCM/FLExDUX4 Preclinical Mouse Model of FSHD.International journal of molecular sciences · 2024Article
- DUX4-induced HSATII transcription causes KDM2A/B-PRC1 nuclear foci and impairs DNA damage response.The Journal of cell biology · 2024Article
- Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation.iScience · 2024Article
- Flavones provide resistance to DUX4-induced toxicity via an mTor-independent mechanism.Cell death & disease · 2023Article
- MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.Cell reports · 2023Article
- Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression.Cell reports · 2023Article
- Molecular and Phenotypic Changes in FLExDUX4 Mice.Journal of personalized medicine · 2023Article
- WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy.Nucleic acids research · 2023Article
- Influence ofInternational journal of molecular sciences · 2023Review
- Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.Brain : a journal of neurology · 2023Article
- DUX4 expression activates JNK and p38 MAP kinases in myoblasts.Disease models & mechanisms · 2022Article
- Proximity ligation assay to detect DUX4 protein in FSHD1 muscle: a pilot study.BMC research notes · 2022Article
- The evolution of DUX4 gene regulation and its implication for facioscapulohumeral muscular dystrophy.Biochimica et biophysica acta. Molecular basis of disease · 2022Review
- Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis.Cell death & disease · 2022Article
- Review
- Downstream events initiated by expression of FSHD-associated DUX4: Studies of nucleocytoplasmic transport, γH2AX accumulation, and Bax/Bak-dependence.Biology open · 2022Article
- Review
- p38 MAPKs - roles in skeletal muscle physiology, disease mechanisms, and as potential therapeutic targets.JCI insight · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
objectivePathogenesis in facioscapulohumeral muscular dystrophy (FSHD) appears to be due to aberrant expression, particularly in skeletal muscle nuclei, of the full-length isoform of DUX4 (DUX4-FL). Expression of DUX4-FL is known to alter gene expression and to be cytotoxic, but cell responses to DUX4-FL are not fully understood. Our study was designed to identify cellular mechanisms of pathogenesis caused by DUX4-FL expression.
methodsWe used human myogenic cell cultures to analyze the effects of DUX4-FL when it was expressed either from its endogenous promoter in FSHD cells or by exogenous expression using BacMam vectors. We focused on determining the effects of DUX4-FL on protein ubiquitination and turnover and on aggregation of TDP-43.
resultsHuman FSHD myotubes with endogenous DUX4-FL expression showed both altered nuclear and cytoplasmic distributions of ubiquitinated proteins and aggregation of TDP-43 in DUX4-FL-expressing nuclei. Similar changes were found upon exogenous expression of DUX4-FL, but were not seen upon expression of the non-toxic short isoform DUX4-S. DUX4-FL expression also inhibited protein turnover in a model system and increased the amounts of insoluble ubiquitinated proteins and insoluble TDP-43. Finally, inhibition of the ubiquitin-proteasome system with MG132 produced TDP-43 aggregation similar to DUX4-FL expression. INTERPRETATIONS: Our results identify DUX4-FL-induced inhibition of protein turnover and aggregation of TDP-43, which are pathological changes also found in diseases such as amyotrophic lateral sclerosis and inclusion body myopathy, as potential pathological mechanisms in FSHD.
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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.