ArticleHuman molecular genetics2017
Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 104 citations in OpenAlex.
- TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.Biochemistry and biophysics reports · 2026Review
- Dysregulated neuronal mRNA transport and translation in FTD/ALS.NPJ dementia · 2026Review
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- TDP-43 promotes efficient HSV-1 replication in human DRG-derived neurons.Journal of virology · 2025Article
- A Duality of Function: An Integrative Model of RACK1 as a Switch Between Translational and Signaling Hubs.International journal of molecular sciences · 2025Review
- The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.Molecular psychiatry · 2025Review
- TDP-43: unveiling the hidden key to cellular fate decisions.Cell communication and signaling : CCS · 2025Review
- Engineered Biomolecular Condensates Limit Tobacco Mosaic Virus Accumulation and Symptom Development.Molecular plant pathology · 2025Article
- Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.Biomedicines · 2025Review
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
- Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.Zoological research · 2025Article
- Optical imaging of metabolic dynamics in ALS under methionine regulation.Journal of biomedical optics · 2025Article
- Insights into the regulation of mRNA translation by scaffolding proteins.Biochemical Society transactions · 2024Review
- Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice.Aging cell · 2024Article
- Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.Acta neuropathologica communications · 2023Article
- Translation dysregulation in neurodegenerative diseases: a focus on ALS.Molecular neurodegeneration · 2023Review
- Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.Molecular neurodegeneration · 2023Review
- The ribosome-associated protein RACK1 represses Kir4.1 translation in astrocytes and influences neuronal activity.Cell reports · 2023Article
- Ribosomal RACK1 Regulates the Dendritic Arborization by Repressing FMRP Activity.International journal of molecular sciences · 2022Article
- Review
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
TDP-43 is a well known RNA binding protein involved in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia (FTLD). In physiological conditions, TDP-43 mainly localizes in the nucleus and shuttles, at least in neurons, to the cytoplasm to form TDP-43 RNA granules. In the nucleus, TDP-43 participates to the expression and splicing of RNAs, while in the cytoplasm its functions range from transport to translation of specific mRNAs. However, if loss or gain of these TDP-43 functions are affected in ALS/FTLD pathogenesis is not clear. Here, we report that TDP-43 localizes on ribosomes not only in primary neurons but also in SH-SY5Y human neuroblastoma cells. We find that binding of TDP-43 to the translational machinery is mediated by an interaction with a specific ribosomal protein, RACK1, and that an increase in cytoplasmic TDP-43 represses global protein synthesis, an effect which is rescued by overexpression of RACK1. Ribosomal loss of RACK1, which excludes TDP-43 from the translational machinery, remarkably reduces formation of TDP-43 cytoplasmic inclusions in neuroblastoma cells. Finally, we corroborate the interaction between TDP-43 and RACK1 on polyribosomes of neuroblastoma cells with mis-localization of RACK1 on TDP-43 positive cytoplasmic inclusions in motor neurons of ALS patients. In conclusions, results from this study suggest that TDP-43 represents a translational repressor not only for specific mRNAs but for overall translation and that its binding to polyribosomes through RACK1 may promote, under conditions inducing ALS pathogenesis, the formation of cytoplasmic inclusions.
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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.