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

Physiological shedding and C-terminal proteolytic processing of TMEM106B.

Cell Rep. 44:115107 (2025)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cp: Cell Biology ; Cp: Neuroscience ; Ftld ; Sppl2a ; Tmem106b ; Cathepsins ; Fibrils ; Luminal Domain ; Lysosomes ; Proteolytic Processing ; Shedding; Frontotemporal Lobar Degeneration; Peptidase-like 2a; Risk-factor; Intramembrane Proteolysis; Sppl2a; Sars-cov-2; Variants; Mutation
Sprache englisch
Veröffentlichungsjahr 2025
Prepublished im Jahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 44, Heft: 1, Seiten: , Artikelnummer: 115107 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) CF Monoclonal Antibodies (CF-MAB)
POF Topic(s) 30201 - Metabolic Health
PSP-Element(e) A-631900-001
Förderungen MRC
DFG
Strategic Neuroscience Funding of the University of Eastern Finland
Sigrid Juselius Foundation
Research Council of Finland
ELA International
Alzheimer's Association through the AD Strategic Fund
BDR
DOI 10.1016/j.celrep.2024.115107
WOS ID 001395098500001
Scopus ID 85212574290
PubMed ID 39709600
Erfassungsdatum 2025-01-09
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