Age-dependent formation of TMEM106B amyloid filaments in human brains

Nature. 2022 May;605(7909):310-314. doi: 10.1038/s41586-022-04650-z. Epub 2022 Mar 28.


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.

MeSH terms

  • Aging*
  • Amyloid beta-Peptides / metabolism
  • Amyloid* / metabolism
  • Amyloidosis* / metabolism
  • Brain* / metabolism
  • Humans
  • Membrane Proteins* / metabolism
  • Nerve Tissue Proteins* / metabolism
  • Plaque, Amyloid / metabolism
  • Tauopathies / metabolism
  • tau Proteins / metabolism


  • Amyloid
  • Amyloid beta-Peptides
  • Membrane Proteins
  • Nerve Tissue Proteins
  • TMEM106B protein, human
  • tau Proteins