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Cited by 38Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsGenetic Neurodegenerative Diseases

C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes

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T. Vicente, Cristina, Perneel, Jolien, Wynants, Sarah, Heeman, Bavo, Van den Broeck, Marleen, Baker, Matt, Cheung, Simon, Faura, Júlia +2 more·2023·Brain
DOI 10.1093/brain/awad133PMC PMC10545506
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Abstract

Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120–254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

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Authors
T. Vicente, C., Perneel, J., Wynants, S., Heeman, B., Van den Broeck, M., Baker, M., Cheung, S., Faura, J., Mackenzie, I. R. A., & Rademakers, R.
Affiliations
  • VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium
  • University of Antwerp (BE)
  • Mayo Clinic in Florida (US)
  • Vancouver Coastal Health (CA)
Corresponding author
  • Mackenzie, Ian R A
  • Rademakers, Rosa
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2023-04-26
Volume
146
Issue
10
Pages
4055-4064
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awad133
PMC
PMC10545506
OpenAlex
W4367041228
Cited by
38
References
2
Citations by year
2026: 7 · 2025: 8 · 2024: 17 · 2023: 6
FWCI
6.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • University of Antwerp Research Funds
  • Vlaams Instituut voor Biotechnologie
  • National Institutes of Health (U19AG063911, UG3 NS103870)
  • Canadian Institutes of Health Research (74580)
  • Research Foundation
  • Holloway Postdoctoral fellowship
  • Association for Frontotemporal Degeneration
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
TMEM106B, C-terminal fragment, progranulin mutations, amyloid fibrils, neurodegenerative diseases, proteinopathies, age-related accumulation, postmortem brain, frontal cortex
MeSH terms
Brain, Haplotypes, Humans, Membrane Proteins, Nerve Tissue Proteins, Cryoelectron Microscopy, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

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