Neurodegeneration risk variants in TMEM106B and GRN converge on a unified molecular mechanism whereby the TMEM106B T185 coding variant impairs degradation of the cleaved intra-lysosomal fibril core domain and progranulin loss amplifies this effect, driving accumulation of neurotoxic TMEM106B amyloid fibrils within lysosomes that are sufficient to cause TDP-43 pathology, neuroinflammation, and neurodegeneration in mice and that rupture lysosomal membranes in human FTLD-GRN brain.

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.