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Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43

Author

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  • Yi Xiao Jiang

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA)

  • Qin Cao

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA
    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)

  • Michael R. Sawaya

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA)

  • Romany Abskharon

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA)

  • Peng Ge

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA)

  • Michael DeTure

    (Mayo Clinic)

  • Dennis W. Dickson

    (Mayo Clinic)

  • Janine Y. Fu

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA)

  • Rachel R. Ogorzalek Loo

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA)

  • Joseph A. Loo

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA)

  • David S. Eisenberg

    (UCLA-DOE Institute, and Molecular Biology Institute, UCLA
    Howard Hughes Medical Institute, UCLA)

Abstract

Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer’s and Parkinson’s diseases1. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills2. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity3. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP4. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.

Suggested Citation

  • Yi Xiao Jiang & Qin Cao & Michael R. Sawaya & Romany Abskharon & Peng Ge & Michael DeTure & Dennis W. Dickson & Janine Y. Fu & Rachel R. Ogorzalek Loo & Joseph A. Loo & David S. Eisenberg, 2022. "Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43," Nature, Nature, vol. 605(7909), pages 304-309, May.
    • Handle: RePEc:nat:nature:v:605:y:2022:i:7909:d:10.1038_s41586-022-04670-9
    DOI: 10.1038/s41586-022-04670-9
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    Cited by:

    1. Yijia Cheng & Jianting Han & Meinai Song & Shuqin Zhang & Qin Cao, 2023. "Serine peptidase Vpr forms enzymatically active fibrils outside Bacillus bacteria revealed by cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Binh An Nguyen & Virender Singh & Shumaila Afrin & Anna Yakubovska & Lanie Wang & Yasmin Ahmed & Rose Pedretti & Maria del Carmen Fernandez-Ramirez & Preeti Singh & Maja Pękała & Luis O. Cabrera Herna, 2024. "Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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