Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition, following only Alzheimer’s and Parkinson’s diseases1. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills2. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TAR DNA-binding protein (TDP-43) immunoreactivity3. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryogenic electron-microscopy (cryo-EM). Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-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, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.

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