Project P3: Identification and mechanistic characterization of a new class of γ-secretase substrates and non-substrates with short extracellular domains

γ-Secretase belongs to the family of intramembrane proteases and has a key function in health and disease. Yet, an in-depth knowledge of the factors governing substrate recognition by γ-secretase is not available.

Addressing this fundamental question is essential to unravel the mechanisms of substrate cleavage, to establish similarities and differences among different intramembrane protease families and for developing substrate-selective protease inhibitors for potential medical use.

Based on our successful work in the first funding period we propose a model for the interaction of γ-secretase with its substrates and their cleavage. Testing this model and thereby unraveling the mechanisms of substrate cleavage is the major aim of our application.

Project P9: Proteomic Platform

The proteomic platform will be an integral part of the research consortium and performs the numerous quantitative mass spectrometry measurements required for projects P1, P2, P3 and P4.

The results of the mass spec analyses will be also relevant for additional projects in the consortium, including the molecular modeling studies.

The platform has two high resolution Orbitrap mass spectrometers (Q Exactive and Q Exactive HF) plus associated equipment, including nanoLCs, and has expertise with the required methods, such as label free quantification and different isotope labelcontaining methods.

The substrate repertoire of γ-secretase/presenilin.

Güner G, Lichtenthaler SF.

Semin Cell Dev Biol. 2020 Sep;105:27-42. doi: 10.1016/j.semcdb.2020.05.019. Epub 2020 Jun 29. PMID: 32616437 Review.

Functions of 'A disintegrin and metalloproteases (ADAMs)' in the mammalian nervous system.

Hsia HE, Tüshaus J, Brummer T, Zheng Y, Scilabra SD, Lichtenthaler SF.

Cell Mol Life Sci. 2019 Jun 24. doi: 10.1007/s00018-019-03173-7. [Epub ahead of print] Review. PMID: 31236626

Degradome of soluble ADAM10 and ADAM17 metalloproteases.

Scharfenberg F, Helbig A, Sammel M, Benzel J, Schlomann U, Peters F, Wichert R, Bettendorff M, Schmidt-Arras D, Rose-John S, Moali C, Lichtenthaler SF, Pietrzik CU, Bartsch JW, Tholey A, Becker-Pauly C.

Cell Mol Life Sci. 2019 Jun 17. doi: 10.1007/s00018-019-03184-4. [Epub ahead of print] PMID: 31209506

NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease.

Brummer T, Müller SA, Pan-Montojo F, Yoshida F, Fellgiebel A, Tomita T, Endres K, Lichtenthaler SF.

EMBO Mol Med. 2019 Apr;11(4). pii: e9695. doi: 10.15252/emmm.201809695. PMID: 30833305

Shedding of BAFF/APRIL Receptors Controls B Cells.

Meinl E, Thaler FS, Lichtenthaler SF.

Trends Immunol. 2018 Sep;39(9):673-676. doi: 10.1016/j.it.2018.07.002. Epub 2018 Jul 30.

Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.

Lichtenthaler SF, Lemberg MK, Fluhrer R.

EMBO J. 2018 Aug 1;37(15). pii: e99456. doi: 10.15252/embj.201899456. Epub 2018 Jul 5. Review.

Click chemistry-mediated biotinylation reveals a function for the protease BACE1 in modulating the neuronal surface glycoproteome

Herber J, Njavro J, Feederle R, Schepers U, Muller U, Brase S, Muller S, Lichtenthaler SF.

Mol Cell Proteomics. 2018.

CADASIL brain vessels show a HTRA1 loss-of-function Profile.

Zellner A, Scharrer E, Arzberger T, Oka C, Domenga-Denier V, Joutel A, Lichtenthaler SF, Muller SA, Dichgans M, Haffner C.

Acta Neuropathol. 2018.

Non-cell-autonomous function of DR6 in Schwann cell Proliferation.

Colombo A, Hsia HE, Wang M, Kuhn PH, Brill MS, Canevazzi P, Feederle R, Taveggia C, Misgeld Th, Lichtenthaler SF (2018).

EMBO J. 2018 Apr 3;37(7),

The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation.

Brummer T, Pigoni M, Rossello A, Wang H, Noy PJ, Tomlinson MG, Blobel CP, Lichtenthaler SF.

FASEB J. 2018:fj201700823RR. 

An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.

Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C.

EMBO Mol Med. 2017 Oct;9(10):1356-1365.

Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue.

Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Müller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K.

Matrix Biol. 2017 May;59:69-79. doi: 10.1016/j.matbio.2016.07.004. Epub 2016 Jul 29. PMID: 27476612

An optimised version of the secretome protein enrichment with click sugars (SPECS) method leads to enhanced coverage of the secretome.

Serdaroglu A, Müller SA, Schepers U, Bräse S, Weichert W, Lichtenthaler SF, Kuhn PH.

Proteomics. 2017 Mar;17(5). doi: 10.1002/pmic.201600423. Epub 2017 Jan 31. PMID: 27991726

MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro.

Baranger K, Bonnet AE, Girard SD, Paumier JM, García-González L, Elmanaa W, Bernard A, Charrat E, Stephan D, Bauer C, Moschke K, Lichtenthaler SF, Roman FS, Checler F, Khrestchatisky M, Rivera S.

Front Mol Neurosci. 2017 Jan 10;9:163. doi: 10.3389/fnmol.2016.00163. eCollection 2016. PMID: 28119565 Free PMC Article

Proteomic Substrate Identification for Membrane Proteases in the Brain.

Müller SA, Scilabra SD, Lichtenthaler SF.

Front Mol Neurosci. 2016 Oct 13;9:96. eCollection 2016. Review. PMID: 27790089 Free PMC Article

Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.

Pigoni M, Wanngren J, Kuhn PH, Munro KM, Gunnersen JM, Takeshima H, Feederle R, Voytyuk I, De Strooper B, Levasseur MD, Hrupka BJ, Müller SA, Lichtenthaler SF.

Mol Neurodegener. 2016 Oct 5;11(1):67. PMID: 27716410 Free PMC Article

Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function.

Kuhn PH, Colombo AV, Schusser B, Dreymueller D, Wetzel S, Schepers U, Herber J, Ludwig A, Kremmer E, Montag D, Müller U, Schweizer M, Saftig P, Bräse S, Lichtenthaler SF.

Elife. 2016 Jan 23;5. pii: e12748. doi: 10.7554/eLife.12748. PMID: 26802628 Free PMC Article

"Generation and deposition of Aβ43 by the virtually inactive presenilin‐1 L435F mutant contradicts the presenilin loss‐of‐function hypothesis of Alzheimer's disease."

Kretner, B., Trambauer, J., Fukumori, A., Mielke, J., Kuhn, P-H., Kremmer, E., Giese, A. , Lichtenthaler, S.F., Haass, C., Arzberger, T., Steiner, H. (2016):

EMBO Molecular Medicine. 2016. e201505952.

all FOR2290 Publications