Schweighauser, ManuelArseni, DianaBacioglu, MehtapHuang, MelissaLövestam, SofiaShi, YangYang, YangZhang, WenjuanKotecha, AbhayGarringer, Holly J.Vidal, RubenHallinan, Grace I.Newell, Kathy L.Tarutani, AiriMurayama, ShigeoMiyazaki, MasayukiSaito, YukoYoshida, MariHasegawa, KazukoLashley, TammarynRevesz, TamasKovacs, Gabor G.van Swieten, JohnTakao, MasakiHasegawa, MasatoGhetti, BernardinoSpillantini, Maria GraziaRyskeldi-Falcon, BenjaminMurzin, Alexey G.Goedert, MichelScheres, Sjors H.W.2023-06-272023-06-272022Schweighauser M, Arseni D, Bacioglu M, et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature. 2022;605(7909):310-314. doi:10.1038/s41586-022-04650-zhttps://hdl.handle.net/1805/33979Many 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.en-USAttribution 4.0 InternationalCryoelectron microscopyMolecular neuroscienceAmyloidosisMembrane proteinsNerve tissue proteinsTauopathiesArticle