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Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G

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Abstract

Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.

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Data availability

Cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) with accession numbers: EMD-19926; EMD-19927; EMD-19928. Corresponding refined atomic models have been deposited in the Protein Data Bank (PDB) under the following accession numbers: 9ERM, 9ERN, 9ERO. Please address requests for materials to the corresponding authors.

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Acknowledgements

This work was supported by the Electron Microscopy Facility of the MRC Laboratory of Molecular Biology. We thank Jake Grimmett, Toby Darling and Ivan Clayson for help with high-performance computing, and Takumi Kitaoka and Mitsuru Futakuchi (Yamagata University School of Medicine) for help with neuropathology. We also thank Hiroya Naruse and Tatsushi Toda (University of Tokyo) for genomic analysis. For open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author-Accepted Manuscript version arising.

Funding

This work was supported by the UK Medical Research Council (MC_UP_A025-1013 to S.H.W.S. and MC_U105184291 to M.G.), the Japanese Society for the Promotion of Science (JSPS KAKENHI and JP20K07922, to R.K. and S.K.) and the Japanese Ministry of Health, Labour and Welfare (JPMH20GB1002 and JPMH23GB1003, to R.K. and S.K.).

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Author notes

  1. Chao Qi and Ryota Kobayashi have contributed equally to this work.

Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Chao Qi, Sjors H. W. Scheres & Michel Goedert

  2. Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan

    Ryota Kobayashi

  3. Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan

    Shinobu Kawakatsu

  4. Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Fuyuki Kametani & Masato Hasegawa

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  1. Chao Qi
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  2. Ryota Kobayashi
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Contributions

RK and SK identified the patient and performed genetic analysis and neuropathology; MH prepared filaments and performed immunoblots; CQ performed cryo-EM data acquisition and structure determination; SHWS, MG and MH supervised the project and all authors contributed to the writing of the manuscript.

Corresponding authors

Correspondence to Sjors H. W. Scheres, Michel Goedert or Masato Hasegawa.

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The authors declare that they have no conflicts of interest.

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Studies carried out at Yamagata University were approved through the Institution’s ethical review process.

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Informed consent was obtained from the patient’s next of kin. This study was approved by the Cambridgeshire 2 Research Ethics Committee (09/H0308/163).

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401_2024_2741_MOESM1_ESM.tif

Supplementary file1 (TIF 23627 KB) Fourier shell correlation (FSC) curves. FSC curves of cryo-EM maps (left panel) and model to map validation (right panel). a, CTE Type I tau filament from VT; CTE Type II tau filament from VT; CTE Type III tau filament from VT

401_2024_2741_MOESM2_ESM.tif

Supplementary file2 (TIF 9588 KB) Double-labelling immunofluorescence using anti-tau and anti-glial fibrillary acid protein antibodies. Sections of frontal cortex from the individual with mutation D395G in VCP were labelled with: a, anti-tau antibody AT8 (green) and anti-glial fibrillary acidic protein antibody (red); b, anti-tau antibody pS396 (red) and anti-glial fibrillary acidic protein antibody (green). DAPI nuclear staining is in blue. There was no evidence for the co-localisation of AT8, pS396 and glial fibrillary acidic protein. Scale bar, 50 m

Supplementary file3 (DOCX 24 KB)

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Qi, C., Kobayashi, R., Kawakatsu, S. et al. Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G. Acta Neuropathol 147, 86 (2024). https://doi.org/10.1007/s00401-024-02741-x

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