ArticleHuman molecular genetics2012
The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers, 1 of them a synthesis that pooled it.
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Who cites it
153 citing papers in PubMed, 1 synthesis or guideline pooled it, 246 citations in OpenAlex.
- Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database.Disease models & mechanisms · 2022Pooled it
- Multiple motor proteins regulate TDP-43 anterograde axonal transport.Acta neuropathologica · 2026Article
- Review
- Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- TDP-43 directly inhibits mRNA accumulation in neurites through modulation of mRNA stability.The EMBO journal · 2026Article
- Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS).Cell death & disease · 2026Article
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism.Acta neuropathologica communications · 2025Article
- Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.Nature neuroscience · 2025Article
- Local Protein Synthesis at Synapses: A Driver for Synapse Diversification.Journal of neurochemistry · 2025Review
- Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924.Scientific reports · 2025Article
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- Dysbiosis and Neurodegeneration in ALS: Unraveling the Gut-Brain Axis.Neuromolecular medicine · 2025Review
- Identification of novel small molecule chaperone activators for neurodegenerative disease treatment.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.Zoological research · 2025Article
- Perivascular phosphorylated TDP-43 inclusions are associated with Alzheimer's disease pathology and loss of CD146 and Aquaporin-4.Brain pathology (Zurich, Switzerland) · 2025Article
- Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.Nature reviews. Neurology · 2025Review
- Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.Experimental neurology · 2025Article
93 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
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Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease specifically affecting cortical and spinal motor neurons. Cytoplasmic inclusions containing hyperphosphorylated and ubiquitinated TDP-43 are a pathological hallmark of ALS, and mutations in the gene encoding TDP-43 have been directly linked to the development of the disease. TDP-43 is a ubiquitous DNA/RNA-binding protein with a nuclear role in pre-mRNA splicing. However, the selective vulnerability and axonal degeneration of motor neurons in ALS pose the question of whether TDP-43 may have an additional role in the regulation of the cytoplasmic and axonal fate of mRNAs, processes important for neuron function. To investigate this possibility, we have characterized TDP-43 localization and dynamics in primary cultured motor neurons. Using a combination of cell imaging and biochemical techniques, we demonstrate that TDP-43 is localized and actively transported in live motor neuron axons, and that it co-localizes with well-studied axonal mRNA-binding proteins. Expression of the TDP-43 C-terminal fragment led to the formation of hyperphosphorylated and ubiquitinated inclusions in motor neuron cell bodies and neurites, and these inclusions specifically sequestered the mRNA-binding protein HuD. Additionally, we showed that overexpression of full-length or mutant TDP-43 in motor neurons caused a severe impairment in axon outgrowth, which was dependent on the C-terminal protein-interacting domain of TDP-43. Taken together, our results suggest a role of TDP-43 in the regulation of axonal growth, and suggest that impairment in the post-transcriptional regulation of mRNAs in the cytoplasm of motor neurons may be a major factor in the development of ALS.
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