ArticleActa neuropathologica2018
Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients.
Article in Acta neuropathologica, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 62 citations in OpenAlex.
- Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.Research square · 2026Article
- Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer's disease.Frontiers in aging neuroscience · 2026Article
- Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.Human molecular genetics · 2025Article
- Mechanisms underlining R-loop biology and implications for human disease.Frontiers in cell and developmental biology · 2025Review
- Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.Neuroscience bulletin · 2024Review
- Prognostic Value of an Immune Long Non-Coding RNA Signature in Liver Hepatocellular Carcinoma.Journal of microbiology and biotechnology · 2024Article
- R-loop and diseases: the cell cycle matters.Molecular cancer · 2024Review
- Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.Journal of neuromuscular diseases · 2024Article
- Increased nuclear import characterizes aberrant nucleocytoplasmic transport in neurons from patients with spinocerebellar ataxia type 7.Frontiers in molecular neuroscience · 2024Article
- Role of Senataxin in Amyotrophic Lateral Sclerosis.Journal of molecular neuroscience : MN · 2023Review
- Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.Cell death & disease · 2023Article
- Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.Acta neuropathologica communications · 2023Article
- Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice.Neurobiology of aging · 2023Article
- Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor.Nucleic acids research · 2023Article
- Clinically relevant mouse models of Charcot-Marie-Tooth type 2S.Human molecular genetics · 2023Article
- Unraveling the impact of disrupted nucleocytoplasmic transport systems inFrontiers in cellular neuroscience · 2023Review
- Protein condensation diseases: therapeutic opportunities.Nature communications · 2022Review
- Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.Brain : a journal of neurology · 2022Article
- Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.Biology · 2022Review
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16 authors at 7 institutions in 5 countries.
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Abstract
Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.
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