Медицинская библиотека · bioRxiv : the preprint server for biology · 2026

Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.

Replogle John Michael, Marks Jordan D, Fernandez Martin G, Yuan Hebao, Yu Dahyun, Winters Elizabeth, Jawahar Vidhya Maheswari, Deshmukh Rishi, Sutanto Renaldo, Kowal Isabelle, Frankenfield Ashley, Shi Rachel, Carlomagno Yari, Jansen-West Karen, Todd Tiffany W, Kopach Andrii, Sandra Ndayambaje Iradukunda, Qi Yue A, Shantaraman Ananth, Pozo-Cabanell Ignacio, Sheth Udit, Yue Mei, Duong Duc, Ferguson Shawn M, Bennett David A, Damme Markus, Boeve Brad F, Day Gregory S, Kellman Benjamin, Skarnes William C, Petersen Ronald C, Josephs Keith A, Graff-Radford Neill R, McDonough Justin A, Prudencio Mercedes, Barmada Sami J, Zhang Yongjie, Hao Ling, DeTure Michael, Rawlinson Bailey, Engelberg-Cook Erica, Casey Monica Castanedes, Perez Nathan, Dickson Dennis W, Wingo Aliza, Liu Yue, Seyfried Nicholas T, Wingo Thomas S, Mosalaganti Shyamal, Petrucelli Leonard, Ward Michael E

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Аннотация

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.

Для цитирования: Replogle John Michael, Marks Jordan D, Fernandez Martin G, Yuan Hebao, Yu Dahyun, Winters Elizabeth, Jawahar Vidhya Maheswari, Deshmukh Rishi, Sutanto Renaldo, Kowal Isabelle, Frankenfield Ashley, Shi Rachel, Carlomagno Yari, Jansen-West Karen, Todd Tiffany W, Kopach Andrii, Sandra Ndayambaje Iradukunda, Qi Yue A, Shantaraman Ananth, Pozo-Cabanell Ignacio, Sheth Udit, Yue Mei, Duong Duc, Ferguson Shawn M, Bennett David A, Damme Markus, Boeve Brad F, Day Gregory S, Kellman Benjamin, Skarnes William C, Petersen Ronald C, Josephs Keith A, Graff-Radford Neill R, McDonough Justin A, Prudencio Mercedes, Barmada Sami J, Zhang Yongjie, Hao Ling, DeTure Michael, Rawlinson Bailey, Engelberg-Cook Erica, Casey Monica Castanedes, Perez Nathan, Dickson Dennis W, Wingo Aliza, Liu Yue, Seyfried Nicholas T, Wingo Thomas S, Mosalaganti Shyamal, Petrucelli Leonard, Ward Michael E. Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.. bioRxiv : the preprint server for biology. 2026. DOI: 10.64898/2026.03.26.714634.

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