TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

Topic: Brain proteins, microglia and lab models

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene.

Key findings

• Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts.
• Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene.
• TDP-43 Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons.
• Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene.

Why it matters

This study created a TDP-43 knock-in mouse with a human-equivalent mutation and found cognitive dysfunction, loss of parvalbumin interneurons and perturbed autoregulation. It is animal research, so it does not establish a treatment or cure for people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41593-018-0113-5
• PubMed: 29556029
• Original source →
• Free full text: Research Portal (King's College London) →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{white2018-29556029,
  author  = {White, M. A. and Kim, E. and Duffy, A. and Adalbert, R. and Phillips, B. U. and Peters, O. M. and Stephenson, J. and Yang, S. and others},
  title   = {{TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD}},
  journal = {Nature neuroscience},
  year    = {2018},
  doi     = {10.1038/s41593-018-0113-5},
  pmid    = {29556029},
  url     = {https://doi.org/10.1038/s41593-018-0113-5}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 15.

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice Nature · 2017-04-12 · usefulness score 61/100 · Lewy body dementia
• Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis Nature neuroscience · 2014-03-30 · usefulness score 58/100 · Lewy body dementia
• Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia Nature genetics · 2005-07-24 · usefulness score 57/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• The frontotemporal dementia-motor neuron disease continuum Lancet (London, England) · 2016-03-14 · usefulness score 56/100 · Getting a diagnosis
• TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Annals of neurology · 2009-04-01 · usefulness score 54/100 · Brain tissue and pathology
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity The Journal of biological chemistry · 2009-05-22 · usefulness score 53/100 · Lewy body dementia
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100 · Lewy body dementia

Later studies that cite this one

12 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Animal models of neurodegenerative diseases Nature neuroscience · 2018-09-24 · usefulness score 57/100 · Lewy body dementia
• TDP-43 proteinopathies: a new wave of neurodegenerative diseases Journal of neurology, neurosurgery, and psychiatry · 2020-11-11 · usefulness score 54/100 · Lewy body dementia
• Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis Disease Models & Mechanisms · 2025-08-01 · usefulness score 49/100 · Lewy body dementia
• Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation Nature reviews. Neuroscience · 2021-03-02 · usefulness score 49/100 · Brain tissue and pathology
• A stress-dependent TDP-43 SUMOylation program preserves neuronal function Molecular Neurodegeneration · 2025-03-28 · usefulness score 48/100 · Brain tissue and pathology
• Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis Neurobiology of disease · 2021-03-31 · usefulness score 46/100 · Brain tissue and pathology
• Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects Science Advances · 2025-04-16 · usefulness score 44/100 · Lewy body dementia

Related studies in Brain tissue and pathology

• Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence Acta Neuropathologica Communications · 2025-03-08 · usefulness score 44/100
• A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD Molecular Therapy · 2025-06-14 · usefulness score 36/100
• Defining the Intestinal eCBome and Oxylipin Signaling Systems in a TDP‐43 Mouse Model of Frontotemporal Dementia The FASEB Journal · 2026-01-12 · usefulness score 41/100
• TDP-43 loss induces cryptic polyadenylation in ALS/FTD Nature Neuroscience · 2025-10-21 · usefulness score 56/100
• ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43 Nature communications · 2014-06-03 · usefulness score 55/100
• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes Nature Neuroscience · 2025-10-21 · usefulness score 55/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Proteomics of the temporal cortex in semantic dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome Acta Neuropathologica Communications · 2025-07-25 · usefulness score 41/100 · Brain tissue and pathology
• TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions The American journal of pathology · 2007-07-01 · usefulness score 59/100 · Lewy body dementia

Similar studies

• Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo 2010 · Lewy body dementia
• TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration 2009 · Lewy body dementia
• TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 2008 · Lewy body dementia
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice 2011 · Lewy body dementia
• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets 2015 · Brain tissue and pathology
• Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD 2019 · Brain tissue and pathology

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