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Cited by 150Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchPrion Diseases and Protein Misfolding

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

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Chang, Andrew, Xiang, Xinyu, Wang, Jing, Lee, Carolyn, Arakhamia, Tamta, Simjanoska, Marija, Wang, Chi, Carlomagno, Yari +15 more·2022·Cell
DOI 10.1016/j.cell.2022.02.026PMC PMC9018563
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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.

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  • There were no significant changes in TMEM106B and MLKL in AD brains.

    “we examined TMEM106B 101-103 and necroptosis effector MLKL 104,105 (Fig. 5c-d), two molecules previously implicated in neurodegeneration of AD, and detected no significant changes.”

    From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [101]

    The Discussion says TMEM106B fibrils were not observed in the authors’ previous Alzheimer’s disease studies, but it does not report a statistical comparison of TMEM106B levels in AD brains. Searches for significant changes and MLKL found no relevant results in our copy; the cited paper therefore does not establish the claimed lack of significant changes. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

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Authors
Chang, A., Xiang, X., Wang, J., Lee, C., Arakhamia, T., Simjanoska, M., Wang, C., Carlomagno, Y., Zhang, G., Dhingra, S., Thierry, M., Perneel, J., Heeman, B., Forgrave, L. M., DeTure, M., DeMarco, M. L., Cook, C. N., Rademakers, R., Dickson, D. W., Petrucelli, L., Stowell, M. H. B., Mackenzie, I. R. A., & Fitzpatrick, A. W. P.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Columbia University (US)
  • Mayo Clinic (US)
  • Weill Cornell Medicine (US)
  • Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
  • New York University (US)
  • University of Antwerp (BE)
  • Providence Health Care (CA)
  • University of Colorado Boulder (US)
  • University of British Columbia (CA)
Corresponding author
  • Stowell, Michael H.B.
  • Mackenzie, Ian R.A.
  • Fitzpatrick, Anthony W.P.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2022-04
Volume
185
Issue
8
Pages
1346-1355.e15
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2022.02.026
PMC
PMC9018563
OpenAlex
W4214871091
Cited by
150
References
10
Citations by year
2026: 20 · 2025: 30 · 2024: 45 · 2023: 40 · 2022: 14
FWCI
20.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Institutes of Health Research (74580)
  • National Institute on Aging (R01AG063780, RF1AG061829)
  • National Institute of Neurological Disorders and Stroke (U01NS110438, P01NS084974, U54NS110435)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
TMEM106B, amyloid fibrils, neurodegenerative diseases, TDP-43, tau protein, alpha-synuclein, frontotemporal lobar degeneration, progressive supranuclear palsy, dementia with Lewy bodies, protein aggregation, lysosomal proteins, cryo-EM structure, postmortem brain
MeSH terms
Amyloid, DNA-Binding Proteins, Humans, Membrane Proteins, Nerve Tissue Proteins, Neurodegenerative Diseases, Cryoelectron Microscopy, Frontotemporal Dementia

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