@article{592b5bfa46954db3b84a394ec7ae2ad5,
title = "Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases",
abstract = "Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 {\AA} from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.",
keywords = "DLB, FTLD-TDP, PSP, TMEM106B, amyloid fibrils, cryo-EM, endosome, lysosome, neurodegeneration, proteolysis",
author = "Andrew Chang and Xinyu Xiang and Jing Wang and Carolyn Lee and Tamta Arakhamia and Marija Simjanoska and Chi Wang and Yari Carlomagno and Guoan Zhang and Shikhar Dhingra and Manon Thierry and Jolien Perneel and Bavo Heeman and Forgrave, {Lauren M.} and Michael DeTure and DeMarco, {Mari L.} and Cook, {Casey N.} and Rosa Rademakers and Dickson, {Dennis W.} and Leonard Petrucelli and Stowell, {Michael H.B.} and Mackenzie, {Ian R.A.} and Fitzpatrick, {Anthony W.P.}",
note = "Funding Information: The authors are grateful to Dr. R.S. Mann for helpful discussions and to the patients and their families for their participation in this work. Human biological samples and associated data were obtained from the Mayo Clinic Brain Bank and UBC. This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke (U01NS110438 to L.P. and A.W.P.F, U54NS110435 to D.W.D. and A.W.P.F.); the Association for Frontotemporal Degeneration; Canadian Institutes of Health Research (74580 to I.R.A.M.); MCDB Neurodegenerative Disease Fund (to M.H.B.S.). The authors are grateful to Simon Cheung for performing IHC, Dr. H. Uryu for electron microscopy, Drs. X. Chen and K. Song for help collecting data on the Titan Krios at the University of Massachusetts Medical School Cryo-EM Core Facility, and R. Grassucci and Dr. Z. Zhang for help collecting data at the Columbia University Cryo-Electron Microscopy Center including the Titan Krios housed at the Zuckerman Institute and the Titan Krios housed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy (New York Structural Biology Center). This paper is dedicated to the memory of Mr. Patrick Trainor. A.W.P.F. I.R.A.M. and M.H.B.S. conceived the experiments. I.R.A.M. identified patients and performed neuropathology on FTLD-TDP cases and PSP cases 2 and 3. D.W.D. and M.D. identified patients and performed neuropathology on PSP case 1. A.W.P.F. and C.L. purified amyloid fibrils from FTLD-TDP cases, PSP cases 2 and 3, and DLB. A.W.P.F. and C.L. performed western blots on sarkosyl-insoluble pellets fractionated from FTLD-TDP, DLB, and non-pathological tissue samples. Y.C. purified amyloid fibrils from PSP case 1. A.W.P.F. J.W. and C.W. performed cryo-EM experiments. A.W.P.F. A.C. X.X. J.W. T.A. and M.S. processed cryo-EM data. A.W.P.F. C.L. and G.Z. performed and analyzed mass spectrometry experiments. Y.C. D.W.D. and L.P. provided a PSP fibril sample. J.P. B.H. L.M.F. M.L.D. and R.R. made intellectual contributions. R.R. performed genetic analyses on all FTLD-TDP cases. A.W.P.F. X.X. J.W. and M.H.B.S. built and refined atomic models. A.W.P.F. A.C. X.X. J.W. T.A. M.S. S.D. M.T. C.N.C. R.R. D.W.D. L.P. M.H.B.S. and I.R.A.M. prepared the manuscript. M.H.B.S. I.R.A.M. and A.W.P.F. supervised the project. The authors declare no competing interests. Funding Information: The authors are grateful to Dr. R.S. Mann for helpful discussions and to the patients and their families for their participation in this work. Human biological samples and associated data were obtained from the Mayo Clinic Brain Bank and UBC. This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke ( U01NS110438 to L.P. and A.W.P.F, U54NS110435 to D.W.D. and A.W.P.F.); the Association for Frontotemporal Degeneration ; Canadian Institutes of Health Research ( 74580 to I.R.A.M.); MCDB Neurodegenerative Disease Fund (to M.H.B.S.). The authors are grateful to Simon Cheung for performing IHC, Dr. H. Uryu for electron microscopy, Drs. X. Chen and K. Song for help collecting data on the Titan Krios at the University of Massachusetts Medical School Cryo-EM Core Facility, and R. Grassucci and Dr. Z. Zhang for help collecting data at the Columbia University Cryo-Electron Microscopy Center including the Titan Krios housed at the Zuckerman Institute and the Titan Krios housed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy (New York Structural Biology Center). This paper is dedicated to the memory of Mr. Patrick Trainor. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = apr,
day = "14",
doi = "10.1016/j.cell.2022.02.026",
language = "English (US)",
volume = "185",
pages = "1346--1355.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "8",
}