Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Cell. 2022 Apr 14;185(8):1346-1355.e15. doi: 10.1016/j.cell.2022.02.026. Epub 2022 Mar 4.


Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Keywords: DLB; FTLD-TDP; PSP; TMEM106B; amyloid fibrils; cryo-EM; endosome; lysosome; neurodegeneration; proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid
  • Cryoelectron Microscopy
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Dementia* / pathology
  • Humans
  • Membrane Proteins* / metabolism
  • Nerve Tissue Proteins* / metabolism
  • Neurodegenerative Diseases*


  • Amyloid
  • DNA-Binding Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • TMEM106B protein, human