Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

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 Å 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. [Display omitted] •Cryo-EM structures of brain-derived TMEM106B fibrils from neurodegenerative diseases•Endolysosomal membrane protein TMEM106B C-terminal fragment forms amyloid fibrils•TMEM106B fibrillization is widespread among diverse neurodegenerative proteinopathies•Identification of fibrillization pathway potentially implicated in neurodegeneration Cryo-EM and mass spectrometry-based proteomics of insoluble amyloid fibrils derived from postmortem human brains afflicted with diverse neurodegenerative diseases reveals widespread fibrillization of an endolysosomal membrane protein, TMEM106B, pointing toward a potentially pathogenic commonality between distinct proteinopathies.