7SAQ

Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1

Summary for 7SAQ

• Entry DOI: 10.2210/pdb7saq/pdb
• EMDB information: 24953
• Descriptor: Transmembrane protein 106B, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: tmem106b, ftld-tdp, amyloid, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 160205.75

Authors

Cao, Q.,Jiang, Y.,Sawaya, M.R.,Eisenberg, D.S. (deposition date: 2021-09-23, release date: 2022-03-09, Last modification date: 2024-11-20)

Primary citation

Jiang, Y.X.,Cao, Q.,Sawaya, M.R.,Abskharon, R.,Ge, P.,DeTure, M.,Dickson, D.W.,Fu, J.Y.,Ogorzalek Loo, R.R.,Loo, J.A.,Eisenberg, D.S.
Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43.
Nature, 605:304-309, 2022

PubMed Abstract: Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity. 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-TDP. 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.

PubMed: 35344984
DOI: 10.1038/s41586-022-04670-9

Experimental method

ELECTRON MICROSCOPY (2.9 Å)