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Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging

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Abstract

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer’s disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population.

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Acknowledgements

This work was funded by grants from the Canadian Institutes of Health Research (74580) and the National Institutes of Health (UAG063911) (IRAM); the University of Antwerp Research Funds (BOF), Vlaams Instituut voor Biotechnologie (VIB), and the National Institutes of Health (UG3 NS103870) (RR). J.P. is supported by a fellowship from Research Foundation—Flanders (FWO). J.F. is supported by a Holloway Postdoctoral fellowship from the Association for Frontotemporal Degeneration (AFTD). We would like to thank Manuel Gödan for excellent technical assistance.

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Authors and Affiliations

  1. VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

    Jolien Perneel, Bavo Heeman, Marleen Van den Broeck, Sarah Wynants, Cristina T. Vicente, Júlia Faura & Rosa Rademakers

  2. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Jolien Perneel, Bavo Heeman, Marleen Van den Broeck, Sarah Wynants, Cristina T. Vicente, Júlia Faura & Rosa Rademakers

  3. Department of Neuropathology, University of Tübingen, Tübingen, Germany

    Manuela Neumann

  4. Molecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany

    Manuela Neumann

  5. Department of Pathology, Vancouver Coastal Health, Vancouver, BC, Canada

    Simon Cheung & Ian R. A. Mackenzie

  6. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Matt Baker & Rosa Rademakers

  7. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Ian R. A. Mackenzie

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Dr. Rademakers is a member of the Scientific Advisory Board of Arkuda Therapeutics and receives invention royalties from a patent related to progranulin. Dr. Mackenzie is a member of the Scientific Advisory Board of Prevail Therapeutics and receives invention royalties from a patent related to progranulin.

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The original online version of this article has been revised. Table 3 and 4 formatting are corrected.

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Supplementary file1 (DOCX 32 KB)

401_2022_2531_MOESM2_ESM.tiff

Supplementary file2 SB0051 recognizes TMEM106B C-terminal fragments but not full-length TMEM106B. Immunoblot was performed on samples from two representative cases (case 106 and 108) under conditions optimized for the detection of TMEM106B C-terminal fragments (CTF) (~30 kDa) (a) and for the detection of full-length TMEM106B (~43 kDa) (b, c). SB0051 detected CTFs in the sarkosyl-insoluble fraction only (a) and did not detected full-length TMEM106B in any of the fractions, even when conditions were optimized for the detection of the full-length protein (b). Full-length TMEM106B was detected in all fractions using an antibody that recognizes an N-terminal epitope of TMEM106B (c). S1 and S3, soluble fractions; P3, sarkosyl-insoluble fraction (TIFF 2171 KB)

401_2022_2531_MOESM3_ESM.tif

Supplementary file3 Comparison of TMEM106B C-terminal antibodies. The novel antiserum (SB0051) (a) and two commercially available antibodies raised against peptides corresponding to regions within the filament forming C-terminal fragment of TMEM106B (LSBio LS-C757550 (b) and Sigma SAB2106773 (c)) each demonstrated intracellular accumulation of material in sections of frontal cortex using standard IHC techniques in cases previously shown to have TMEM106B (120-254) filaments by cryo-EM [5]. Frontal cortex of case 7. Scale bar, 40 µm (TIF 7351 KB)

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Perneel, J., Neumann, M., Heeman, B. et al. Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging. Acta Neuropathol 145, 285–302 (2023). https://doi.org/10.1007/s00401-022-02531-3

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