MassIVE MSV000088430

Complete Public PXD029876

Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B, rather than TDP-43

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Description

FTLD is the third most common neurodegenerative condition, following only Alzheimer's and Parkinson's diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TDP-43 immunoreactivity. 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 cryo-EM. Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of TMEM106B, a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. 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. [doi:10.25345/C5528S] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMEM106B ; amyloid ; fibril ; FTLD-TDP

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Principal Investigators:
(in alphabetical order) 		Joseph Loo, University of California Los Angeles, United States
Submitting User: janinefu
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