Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence

Topic: Brain proteins, microglia and lab models

TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.

Key findings

• Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors.
• Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.

Why it matters

A new knock-in mouse model expressing mislocalized TDP-43 showed DNA repair impairment, inflammation, cellular senescence and motor deficits. The authors suggest it opens avenues for developing DNA repair-targeted approaches, but this is animal research and no treatment has been tested in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-01962-9
• PubMed: 40057796
• Original source →
• Free full text: Acta Neuropathologica Communications →

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

@article{mitra2025-40057796,
  author  = {Mitra, Joy and Kodavati, Manohar M. and Dharmalingam, Prakash and Guerrero, Erika N. and Rao, K. S. Jagannatha and Garruto, Ralph M. and Hegde, Muralidhar L.},
  title   = {{Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-01962-9},
  pmid    = {40057796},
  url     = {https://doi.org/10.1186/s40478-025-01962-9}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 16.

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia Brain : a journal of neurology · 2016-11-01 · usefulness score 63/100 · Getting a diagnosis
• 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
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · 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
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology
• 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
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · Lewy body dementia

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