Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia, Marija Simjanoska, Chi Wang, Yari Carlomagno, Guoan Zhang, Shikhar Dhingra, Manon Thierry, Jolien Perneel, Bavo Heeman, Lauren M. Forgrave, Michael DeTure, Mari L. DeMarco, Casey Cook, Rosa Rademakers, Dennis W. Dickson, Leonard PetrucelliMichael H.B. Stowell, Ian R.A. Mackenzie, Anthony W.P. Fitzpatrick

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)1346-1355.e15
JournalCell
Volume185
Issue number8
DOIs
StatePublished - Apr 14 2022

Keywords

  • DLB
  • FTLD-TDP
  • PSP
  • TMEM106B
  • amyloid fibrils
  • cryo-EM
  • endosome
  • lysosome
  • neurodegeneration
  • proteolysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases'. Together they form a unique fingerprint.

Cite this