ArticleActa neuropathologica2015
Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.
Article in Acta neuropathologica, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 193 papers, 1 of them a synthesis that pooled it.
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Who cites it
193 citing papers in PubMed, 1 synthesis or guideline pooled it, 344 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
- Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial.Nature communications · 2025Trial
- Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Review
- Crossroad of motor neuron disease and dementia: Insights from TDP-43 RNA-binding deficiency.Neural regeneration research · 2026Article
- Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.Nature biomedical engineering · 2026Article
- Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.Nature aging · 2026Article
- Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.Journal of neurology · 2026Review
- Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.Neurology international · 2026Article
- Nuclear dysfunction in aging and neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- A Age Related Vascular Senescence: Mystery of Blood-brain Barrier Dysfunction in Neurodegeneration.Molecular neurobiology · 2026Review
- Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.Nature communications · 2026Article
- Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.Scientific reports · 2026Article
- A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2026Article
- TDP-43 pathology is linked to motor neuron loss and is independent of stress granulesbioRxiv : the preprint server for biology · 2026Article
- Linear ubiquitination of the NMDA receptor GluN2A subunit facilitates the GluN2B-to-GluN2A switch and synaptic maturation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- FGF13 is not secreted from mouse neurons.JCI insight · 2026Article
- Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.Acta neuropathologica communications · 2026Article
- Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.Discovery immunology · 2026Article
- Article
- Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.Open life sciences · 2026Review
133 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these 'regulatable NLS' (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43∆NLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.
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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.