Fig. 3

Disease-associated variants increase TMEM106B levels and induce prion-like aggregation. Genetic variants of TMEM106B cause overexpression of TMEM106B protein. TMEM106B 118–274 residue is cleaved by a protease, and the resulting C-terminal fragment is prone to aggregate. When lysosome function is insufficient, or the production of TMEM106B increased, C-terminal fragments reach the critical point of fibrilization. Cryo-EM micrographs showed that TMEM106B filaments are comprised of two protofilaments. The TMEM106B oligomers serving as ‘seeds’ will recruit or interact with normal TMEM106B proteins, interfering their functions in modulating lysosome biogenesis, thus effectively causing a deficiency of functional TMEM106B. The prion-like aggregation develops into detectable TMEM106B deposits eventually. The aggregation of TMEM106B(120–254) into fibrils further hinders the normal function of TMEM106B protein on the membrane, leading to lysosomal dysfunction, which promotes the accumulation of other pathological protein aggregates such as those formed by TDP-43, tau or a-synuclein and the free TMEM106B fragments(monomer, oligomer, fibril) in the lysosome. Reproduced with the permission of Schweighauser, M. et al., [9]