TDP-43 dysfunction facilitates the pathological conversion of tau.

Authors

Meghraj S Baghel, Grace D Burns, Margarita Tsapatsis, Aswathy Peethambaran Mallika, Anna Lourdes F Cruz, Tianyu Cao, Xiaoke K Chen, Isabel De La Rosa, Shaelyn R Marx, Yingzhi Ye, Shuying Sun, Tong Li, Jonathan P Ling, Philip C Wong

Published in

Molecular neurodegeneration. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbp^f/f mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbp^f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.

PMID:
42401929
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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