Physiological shedding and C-terminal proteolytic processing of TMEM106B
Year: 2024
Type: article
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.
Source: Cell Reports
Authors: Sebastian Held, Christian Erck, Susanna Kemppainen, Florian Bleibaum, Neha Jadhav Giridhar, Regina Feederle, Claudia Krenner, Sini-Pauliina Juopperi, Anna Calliari, Torben Mentrup, Bernd Schröder, Dennis W. Dickson, Tuomas Rauramaa, Leonard Petrucelli, Mercedes Prudencio, Mikko Hiltunen, Patrick Lüningschrör, Anja Capell, Markus Damme
Institutions: Christian-Albrechts-Universität zu Kiel, Helmholtz Centre for Infection Research, University of Eastern Finland, Universitätsklinikum Würzburg, German Center for Neurodegenerative Diseases, Helmholtz Munich, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, Mayo Clinic, Mayo Clinic in Florida, University Hospital Carl Gustav Carus, Technische Universität Dresden, Kuopio University Hospital
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
Awards: G2006516271, G212324775, G2350158006, G4188925906, G472808506, G5183239288, Mechanisms of microglia-specific genetic variants associated with Alzheimer's disease, G5676597991, G7912415199, Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets, Stathmin-2 and TDP-43 neurodegeneration in Alzheimer’s and multi-etiology dementias
OpenAlex ID: W4405671295