| Endothelial type I interferon signaling modulates the vascular response to ischemic brain injury |
Kavli Affiliate: Shawn Ferguson
| Authors: John Michael Replogle, Jordan D Marks, Martin G Fernandez, Hebao Yuan, Belle Yu, Elizabeth Winters, Vidhya Maheswari Jawahar, Rishi Deshmukh, Renaldo Sutanto, Isabelle Kowal, Ashley Frankenfield, Rachel Shi, Yari Carlomagno, Karen Jansen-West, Tiffany Todd, Andrii Kopach, Iradukunda Sandra Ndayambaje, Yue A Qi, Ananth Shantaraman, Ignacio Pozo-Cabanell, Udit Sheth, Mei Yue, Duc Duong, Shawn M Ferguson, David A Bennett, Markus Damme, Brad F Boeve, Gregory S Day, Benjamin Kellman, William C Skarnes, Ronald C Petersen, Keith A Josephs, Neill Graff-Radford, Justin A McDonough, Mercedes Prudencio, Sami J Barmada, Yongjie Zhang, Ling Hao, Michael DeTure, Bailey Rawlinson, Erica Engelberg Cook, Monica Castanedes Casey, Nathan Perez, Dennis Dickson, Aliza Wingo, Yue Liu, Nick T Seyfried, Thomas S Wingo, Shyamal Mosalaganti, Leo nard Petrucelli and Michael E Ward
| Summary:
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.