Age-dependent formation of TMEM106B amyloid filaments in human brains.
Hallinan, Grace I
Newell, Kathy L
van Swieten, John
Spillantini, Maria Grazia
Murzin, Alexey G
Springer Science and Business Media LLC
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Schweighauser, M., Arseni, D., Bacioglu, M., Huang, M., Lövestam, S., Shi, Y., Yang, Y., et al. (2022). Age-dependent formation of TMEM106B amyloid filaments in human brains.. Nature, 605 (7909), 310-314. https://doi.org/10.1038/s41586-022-04650-z
Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.
Article, /631/535/1258/1259, /631/378/340, /101/28, /13/51, article
External DOI: https://doi.org/10.1038/s41586-022-04650-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337089