Hromadkova, Lenka;
Kim, Chae;
Haldiman, Tracy;
Siddiqi, Mohammad Khursheed;
Surewicz, Krystyna;
Urquhart, Kiley;
Sadruddin, Dur-E-Nayab;
... Safar, Jiri G; + view all
(2025)
Structural exposure of different microtubule binding domains determines the propagation and toxicity of pathogenic tau conformers in Alzheimer’s disease.
PLoS Pathogens
, 21
(6)
, Article e1012926. 10.1371/journal.ppat.1012926.
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Abstract
Deposits of misfolded tau proteins are leading indicators of cognitive decline in Alzheimer's disease (AD), and our recent data implicate distinctly misfolded conformers of the tau protein with high seeding potency in rapid progression. We considered prion-like templated propagation of misfolding in neurons as an underlying mechanism and derived sensitive conformational assays to test this concept and identify critical structural drivers. Using novel photochemical hydroxylation monitored with a panel of Europium-labeled monoclonal antibodies, we investigated the structural organization of different microtubule binding domains (MTBDs) in brain-derived tau conformers in AD with different progression rates. We analyzed the impact of structural organization of different MTBDs on seeding potency in vitro and in primary neurons, and on the propagation rate of tau misfolding, compartmentalization, cytotoxicity, and calcium homeostasis in neuronally differentiated SH-SY5Y cells. Within the extensive inter-individual structural variability in all MTBDs and C-terminal tails, the most significant driver of seeding potency and propagation of tau protein misfolding in both in vitro seeding assays and in neuronal cultures was the structural exposure of the fourth MTBD (R4). In contrast, the major driver of calcium influx induced in neurons by the accumulation of misfolded tau was the structural exposure of the R1 domain. The data provide compelling evidence for a major diversity in the structural organization of MTBDs of misfolded AD brain-derived tau protein and implicate the structural exposure of distinct domains in different pathogenetic steps of AD - R4 tau domain in progression rate, and R1 domain in variable synaptic toxicity of misfolded tau, and thus in cognitive decline.
| Type: | Article |
|---|---|
| Title: | Structural exposure of different microtubule binding domains determines the propagation and toxicity of pathogenic tau conformers in Alzheimer’s disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.ppat.1012926 |
| Publisher version: | https://doi.org/10.1371/journal.ppat.1012926 |
| Language: | English |
| Additional information: | © 2025 Hromadkova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209923 |
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