Journal Article

DZNE-2025-00051

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Physiological shedding and C-terminal proteolytic processing of TMEM106B

Held, S. ; Erck, C. ; Kemppainen, S. ; Bleibaum, F. ; Giridhar, N. J. ; Feederle, R.DZNE* ; Krenner, C.Extern* ; Juopperi, S.-P. ; Calliari, A. ; Mentrup, T. ; Schröder, B. ; Dickson, D. W. ; Rauramaa, T. ; Petrucelli, L. ; Prudencio, M. ; Hiltunen, M. ; Lüningschrör, P. ; Capell, A.DZNE* ; Damme, M.

2025
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2024.115107

Abstract: Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear. We developed a commercially available antibody against the luminal domain of TMEM106B, allowing a detailed survey of the proteolytic processing under physiological conditions in cellular models and TMEM106B-related mouse models. Moreover, fibrillary TMEM106B was detected in human autopsy material. We find that the luminal domain is generated by multiple lysosomal cysteine-type proteases. Cysteine-type proteases perform additional C-terminal trimming, for which experimental evidence has been lacking. The presented results allow an in-depth perception of the processing of TMEM106B, a prerequisite to understanding factors leading to fibril formation.

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Contributing Institute(s):

1. Antibody Production (AG Feederle)
2. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
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