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

Nature. 2022 May;605(7909):304-309. doi: 10.1038/s41586-022-04670-9. Epub 2022 Mar 28.


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.

MeSH terms

  • Amyloid* / ultrastructure
  • Cryoelectron Microscopy
  • DNA-Binding Proteins* / metabolism
  • DNA-Binding Proteins* / ultrastructure
  • Frontotemporal Lobar Degeneration* / metabolism
  • Frontotemporal Lobar Degeneration* / pathology
  • Humans
  • Membrane Proteins* / metabolism
  • Membrane Proteins* / ultrastructure
  • Nerve Tissue Proteins* / metabolism
  • Nerve Tissue Proteins* / ultrastructure


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