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. Author manuscript; available in PMC: 2023 Apr 14.
Published in final edited form as: Cell. 2022 Mar 4;185(8):1346–1355.e15. doi: 10.1016/j.cell.2022.02.026

Figure 6. Structure-based model of a possible interrelationship between TMEM106B, aggregated filaments, and lysosomes in neurodegenerative diseases.

Figure 6.

Under physiological conditions, TMEM106B spans the lysosomal/endosomal membrane. Upon cleavage of the C-terminal fragment, TMEM106B(120–254) fibrils may form. It is currently unknown whether TMEM106B(120–254) fibrillizes in the lumen or if lysosomal leakage occurs and TMEM106B(120–254) fragments aggregate into fibrils in the cytosol. Based on our set of TMEM106B fibril structures, we speculate that the aggregation of TMEM106B(120–254) into fibrils leads to lysosomal dysfunction, which promotes the accumulation of aberrantly aggregated amyloid fibrils such as those formed by TDP-43 (PDB:7PY2, green sticks), tau (PDB:7P65, blue sticks), or α-synuclein.