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However, existing transgenic hTDP-43 WT or \u2206NLS-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\u2206NLS variant of mouse Tdp-43. This variant is expressed either in the\u00a0whole 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\u2206NLS 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\u2206NLS 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.<\/jats:p>","DOI":"10.1186\/s40478-025-01962-9","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T05:48:56Z","timestamp":1741412936000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence"],"prefix":"10.1186","volume":"13","author":[{"given":"Joy","family":"Mitra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manohar","family":"Kodavati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Dharmalingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika N.","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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