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.
Signatures of glial activity can be detected in the CSF proteome.
Eninger T, Müller SA, Bacioglu M, Schweighauser M, Lambert M, Maia LF, Neher JJ, Hornfeck SM, Obermüller U, Kleinberger G, Haass C, Kahle PJ, Staufenbiel M, Ping L, Duong DM, Levey AI, Seyfried NT, Lichtenthaler SF, Jucker M, Kaeser SA.
Proc Natl Acad Sci U S A. 2022 Jun 14;119(24):e2119804119. doi: 10.1073/pnas.2119804119. Epub 2022 Jun 6.PMID: 35666874 Free PMC article.
ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion.
Jocher G, Grass V, Tschirner SK, Riepler L, Breimann S, Kaya T, Oelsner M, Hamad MS, Hofmann LI, Blobel CP, Schmidt-Weber CB, Gokce O, Jakwerth CA, Trimpert J, Kimpel J, Pichlmair A, Lichtenthaler SF.
EMBO Rep. 2022 Jun 7;23(6):e54305. doi: 10.15252/embr.202154305. Epub 2022 May 8.PMID: 35527514 Free PMC article.
Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2.
Lichtenthaler SF, Tschirner SK, Steiner H.
Curr Opin Neurobiol. 2022 Feb;72:101-110. doi: 10.1016/j.conb.2021.09.003. Epub 2021 Oct 22. PMID: 34689040 Review.
The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system.
Tüshaus J, Müller SA, Shrouder J, Arends M, Simons M, Plesnila N, Blobel CP, Lichtenthaler SF.FASEB J. 2021 Nov;35(11):e21962. doi: 10.1096/fj.202100936R.PMID: 34613632
Hsia HE, Tüshaus J, Feng X, Hofmann LI, Wefers B, Marciano DK, Wurst W, Lichtenthaler SF.
FASEB J. 2021 Sep;35(9):e21813. doi: 10.1096/fj.202100475R. PMID: 34390512
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.
Rudan Njavro J, Klotz J, Dislich B, Wanngren J, Shmueli MD, Herber J, Kuhn PH, Kumar R, Koeglsperger T, Conrad M, Wurst W, Feederle R, Vlachos A, Michalakis S, Jedlicka P, Müller SA, Lichtenthaler SF.
FASEB J. 2020 Feb;34(2):2465-2482. doi: 10.1096/fj.201902347R. Epub 2019 Dec 27. PMID: 31908000
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.
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.
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),
Brummer T, Pigoni M, Rossello A, Wang H, Noy PJ, Tomlinson MG, Blobel CP, Lichtenthaler SF.
FASEB J. 2018:fj201700823RR.
Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C.
EMBO Mol Med. 2017 Oct;9(10):1356-1365.
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
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
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
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
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
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.