Amyloid fibrils in frontotemporal lobar degeneration with TDP-43 inclusions are composed of TMEM106B, rather than TDP-43

Abstract

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.

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

“…We observe bands consistent with monomeric TMEM106B(120-254), molecular weight of 15.49 kDa, at $16 kDa (Figure S6) and multiple bands $25 kDa (Figure S6) that may correspond to glycosylated TMEM106B(120-254) monomers. Notably, there are many higher molecular weight bands at 110 kDa, 135 kDa, and 190 kDa that are consistent with TMEM106B oligomerization (Jiang et al, 2022) (Figure S6). The general trend we observe is that these high molecular weight species are more abundant in pathological cases compared to non-pathological controls, although there are exceptions (e.g., FTLD-TDP case 4 is a sporadic case that shows a high concentration of TMEM106B fibrils by cryo-EM but not by western blot).…”

“…Importantly, we and others (Jiang et al, 2022) contend that western blots do not reliably detect TMEM106B aggregation. An antibody has recently been generated that detects nonfibrillar TMEM106B by binding to residues (239-250), which are buried in the fibril core (Schweighauser et al, 2021).…”