ArticleActa neuropathologica2020
TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons.
Article in Acta neuropathologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 80 citations in OpenAlex.
- Multiple motor proteins regulate TDP-43 anterograde axonal transport.Acta neuropathologica · 2026Article
- Single-nucleus multiome shows motor neuron glutamate overactivation in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- Robust mammalian RNA localization elements are complex and multipartite.bioRxiv : the preprint server for biology · 2026Article
- TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.Biochemistry and biophysics reports · 2026Review
- TDP-43 directly inhibits mRNA accumulation in neurites through modulation of mRNA stability.The EMBO journal · 2026Article
- Dysregulated neuronal mRNA transport and translation in FTD/ALS.NPJ dementia · 2026Review
- The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.Molecular psychiatry · 2025Review
- Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.Nature neuroscience · 2025Article
- Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Article
- Genetic Basis of Motor Neuron Diseases: Insights, Clinical Management, and Future Directions.International journal of molecular sciences · 2025Review
- Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.The Lancet. Neurology · 2025Review
- Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.Developmental cell · 2025Article
- hnRNP R promotes O-GlcNAcylation of eIF4G and facilitates axonal protein synthesis.Nature communications · 2024Article
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- Review
- FMRP-mediated spatial regulation of physiologic NMD targets in neuronal cells.Genome biology · 2024Review
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
- Review
- Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.Biomedicines · 2023Review
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Authors and funding
18 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.
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