ArticleHuman molecular genetics2015
Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 96 citations in OpenAlex.
- Comparing loss of individual fragile X proteins suggests strong links to cellular senescence and aging.Cellular and molecular life sciences : CMLS · 2025Article
- Small-molecule dissolution of stress granules by redox modulation benefits ALS models.Nature chemical biology · 2025Article
- Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function.Nature communications · 2025Article
- RNA guanine content and G-quadruplex structure tune the phase behavior and material properties of biomolecular condensates.Scientific reports · 2025Article
- Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.Developmental cell · 2025Article
- Beyond the Synapse:International journal of molecular sciences · 2024Review
- Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice.Aging cell · 2024Article
- FMRP-mediated spatial regulation of physiologic NMD targets in neuronal cells.Genome biology · 2024Review
- Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.bioRxiv : the preprint server for biology · 2023Article
- Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits.Acta neuropathologica communications · 2023Article
- The Fragile X Protein Family in Amyotrophic Lateral Sclerosis.Molecular neurobiology · 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
- Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia.Science advances · 2023Article
- Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.Frontiers in molecular neuroscience · 2023Review
- Recognition of the TDP-43 nuclear localization signal by importin α1/β.Cell reports · 2022Article
- Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production.Frontiers in neuroscience · 2022Review
- RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis.International journal of molecular sciences · 2021Review
- ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model.Neurobiology of disease · 2021Article
- ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity.Communications biology · 2021Article
- Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis.Biomedicines · 2021Review
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.
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