Citations 1
Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation
Replogle, John, Marks, Jordan D. , Fernandez, Martin G , Yu, Dahyun , Winters, Elizabeth, Jawahar, Vidhya Maheswari, Deshmukh, Rishi, Sutanto, Renaldo, Kowal, Isabelle, Frankenfield, Ashley M. , Shi, Rachel , Carlomagno, Yari , Jansen-West, Karen, Kopach, Andrii , Ndayambaje, I. Sandra , Qi, Yue Andy, Shantaraman, Ananth, Pozo-Cabanell, Ignacio, Sheth, Udit , Yue, Mei, Duong, Duc, Bennett, David A, Damme, Markus, Boeve, Brad F, Day, Gregory S, Skarnes, William C, Petersen, Ronald C, Josephs, K., Graff-Radford, Neill, Barmada, Sami J. , Zhang, Yongjie, Hao, Ling , DeTure, Michael , Rawlinson, Bailey, Cook, Erica Engelberg, Casey, Monica Castanedes, Perez, Nathan M, Dickson, Dennis, Liu, Yue, Seyfried, Nicholas T., Wingo, Thomas S, Mosalaganti, Shyamal , Petrucelli, Leonard, Ward, Michael E, Ward, Michael E. , Replogle, John Michael , Todd, Tiffany W. , Engelberg-Cook, Erica , Perez, Nathan, Ward, Michael E , Barmada, Sami , Sheth, Udit , Yuan, Hebao , Kowal, Isabelle , Jansen‐West, Karen , Qi, Yue , Shantaraman, Anantharaman , Duong, Duc, Ferguson, Shawn M. , Bennett, David A. , Daμμe, Markus , Day, Gregory S. , Kellman, Benjamin P. , Skarnes, William C. , Petersen, Ronald C. , Graff‐Radford, Neill R. , McDonough, Justin A. , Prudencio, Mercedes , Dickson, Dennis W. , Wingo, Aliza P. , Liu, Yue, Seyfried, Nicholas T. , Wingo, Thomas S , Petrucelli, Leonard
No container title available | March 28, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.