Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

Replogle, J. M.; Marks, J. D.; Fernandez, M. G.; Yuan, H.; Yu, B.; Winters, E.; Jawahar, V. M.; Deshmukh, R.; Sutanto, R.; Kowal, I.; Frankenfield, A.; Shi, R.; Carlomagno, Y.; Jansen-West, K.; Todd, T.; Kopach, A.; Ndayambaje, I. S.; Qi, Y. A.; Shantaraman, A.; Pozo-Cabanell, I.; Sheth, U.; Yue, M.; Duong, D.; Ferguson, S. M.; Bennett, D. A.; Damme, M.; Boeve, B. F.; Day, G. S.; Kellman, B.; Skarnes, W. C.; Petersen, R. C.; Josephs, K. A.; Graff-Radford, N.; McDonough, J. A.; Prudencio, M.; Barmada, S. J.; Zhang, Y.; Hao, L.; DeTure, M.; Rawlinson, B.; Cook, E. E.; Casey, M. C.; Perez, N.; Di

doi:10.64898/2026.03.26.714634

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bioRxiv · 10.64898/2026.03.26.714634

Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

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Abstract

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.

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Replogle, J. M., Marks, J. D., Fernandez, M. G., Yuan, H., Yu, B., Winters, E., Jawahar, V. M., Deshmukh, R., Sutanto, R., Kowal, I., Frankenfield, A., Shi, R., Carlomagno, Y., Jansen-West, K., Todd, T., Kopach, A., Ndayambaje, I. S., Qi, Y. A., Shantaraman, A., Pozo-Cabanell, I., Sheth, U., Yue, M., Duong, D., Ferguson, S. M., Bennett, D. A., Damme, M., Boeve, B. F., Day, G. S., Kellman, B., Skarnes, W. C., Petersen, R. C., Josephs, K. A., Graff-Radford, N., McDonough, J. A., Prudencio, M., Barmada, S. J., Zhang, Y., Hao, L., DeTure, M., Rawlinson, B., Cook, E. E., Casey, M. C., Perez, N., Di. 2026-03-28. Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation. https://doi.org/10.64898/2026.03.26.714634

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