Priv. Doz. Dr. Stefan Lichtenthaler
Group Leader
German Center for Neurodegenerative Diseases (DZNE)
Schillerstr. 44
80336 Munich
stefan.lichtenthaler(at)dzne.de
+49 (0) 89 / 2180-75453
+49 (0) 89 / 2180-75415
More information
Areas of investigation/research focus
We study how membrane proteins are proteolytically cleaved at the cell surface. This process is called regulated intramembrane proteolysis and is a basic cellular mechanism controlling the communication between cells and their environment. Regulated intramembrane proteolysis contributes to numerous biological processes, from signal transduction to cell adhesion and embryonic development. A dysregulation of regulated intramembrane proteolysis is associated with diseases, such as tumors, rheumatoid arthritis and Alzheimer's disease.
Regulated intramembrane proteolysis is a two-step proteolytic cascade. A single-span membrane protein is first cut within its ectodomain (ectodomain shedding) (Fig. 1) and then within its transmembrane domain. An increasing number of proteins are identified as substrates for regulated intramembrane proteolysis, including receptors (e.g. Notch), cytokines (e.g. TNFα) and the amyloid precursor protein (APP), which has a central role in the pathogenesis of Alzheimer's disease. Shedding of APP occurs by distinct proteases called α- or β-secretase. Intramembrane proteolysis is mediated by γ-secretase.
Figure1: Scheme of regulated intramembrane proteolysis (RIP). RIP is a proteolytic cascade, in which a membrane protein (depicted as the vertical grey and white stick) is consecutively cleaved by two distinct membrane proteases (green). The first cleavage (shedding) leads to the secretion of the ectodomain. The remaining, membrane-bound fragment (grey) is further cleaved within its transmembrane domain (intramembrane proteolysis).
The combination of β- and γ-secretase leads to the generation of the pathogenic Aβ peptide (Fig. 2), whereas the cleavage by α-secretase prevents Aβ generation and thus the mechanisms leading to Alzheimer's disease.
We follow three lines of research. First, we study the molecular players - proteases, substrates and mechanisms - involved in regulated intramembrane proteolysis, in order to elucidate the biological function of this process. Second, we investigate how regulated intramembrane proteolysis is controlled in the cell and how it is dysregulated in disease. Third, we aim at identifying new ways to modulate the regulated intramembrane proteolysis in diseases, in particular in Alzheimer's disease. We identify new drug targets, test new pharmacological approaches and search for suitable biomarkers of the disease.
For our research, we use a variety of methods ranging from biochemistry to functional genomics, proteomics and molecular biology, for example lentiviruses and high-throughput cellular screens with siRNA and small molecules.
Figure 2: Proteolytic processing of the the amyloid precursor protein (APP). APP is a membrane-protein. The membrane is depicted as a grey box. APP is proteolytically processed in two pathways. One pathway generates the pathogenic Aβ peptide (indicated as red box), the other one prevents it. Cleavage by the protease β-secretase at the upper end of the Aβ domain leads to the secretion of the APP ectodomain (APPsβ). Subsequently, the protease γ-secretase cuts at the lower end of the Aβ domain, leading to Aβ secretion. In contrast to β-secretase, the protease α-secretase cleaves APP with the Aβ domain, thus preventing Aβ generation. Additionally, it leads to the secretion of the APP ectodomain (APPsα).
Publications
Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking.
Lichtenthaler SF. Curr Alzheimer Res. 2012 Feb 1;9(2):165-77.
Cell biology. Sheddase gets guidance.
Lichtenthaler SF. Science. 2012 Jan 13;335(6065):179-80.
ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein.
ML Moss, G Powell, MA Miller, L Edwards, B Qi, QX Sang, B De Strooper, I Tesseur, SF Lichtenthaler, M Taverna, JL Zhong, C Dingwall, T Ferdous, U Schlomann, P Zhou, LG Griffith, DA Lauffenburger, R Petrovich, JW Bartsch; J Biol Chem. 2011 Nov 25;286(47):40443-51. Epub 2011 Sep 28.
Determination of the Proteolytic Cleavage Sites of the Amyloid Precursor-Like Protein 2 by the Proteases ADAM10, BACE1 and γ-Secretase.
S Hogl, PH Kuhn, A Colombo, SF Lichtenthaler; PLoS One. 2011;6(6):e21337. Epub 2011 Jun 17.
Regulated intramembrane proteolysis--lessons from amyloid precursor protein processing.
SF Lichtenthaler, C Haass, H Steiner; J Neurochem. 2011 Jun;117(5):779-96. doi: 10.1111/j.1471-4159.2011.07248.x. Epub 2011 Apr 14.
Bioinformatics identification of modules of transcription factor binding sites in Alzheimer's disease-related genes by in silico promoter analysis and microarrays.
R Augustin, SF Lichtenthaler, M Greeff, J Hansen, W Wurst, D Trümbach; Int J Alzheimers Dis. 2011 Apr 26;2011:154325.
F-spondin regulates neuronal survival through activation of disabled-1 in the chicken ciliary ganglion.
Peterziel H, Sackmann T, Strelau J, Kuhn PH, Lichtenthaler SF, Marom K, Klar A, Unsicker K, Mol Cell Neurosci. 2011 Feb;46(2):483-97. Epub 2010 Dec 9.
ADAM10: Potential 'molecular scissors for the treatment of Alzheimers disease.
Lichtenthaler SF, Future Neurology January 2011, Vol. 6, No. 1, Pages 1-4 , DOI 10.2217/fnl.10.75
Alpha-secretase in Alzheimer's disease: Molecular identity, regulation and therapeutic potential.
Lichtenthaler SF, J Neurochem. 2011 Jan;116(1):10-21. doi: 10.1111/j.1471-4159.2010.07081.x. Epub 2010 Dec 2.
Specific amino acids in the BAR domain allow homodimerization and prevent heterodimerization of sorting nexin 33.
Dislich B, Than ME, Lichtenthaler SF, Biochem J. 2010 Dec 15;433(1):75-83.
ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.
Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Roßner S, Lichtenthaler SF. (2010), EMBO J. 2010 Sep 1;29(17):3020-32. Epub 2010 Jul 30.
The transmembrane protein 147 (TMEM147) is a novel component of the nicalin-nomo protein complex.
U Dettmer, PH Kuhn, C Abou-Ajram, SF Lichtenthaler, M Krueger, E Kremmer, C Haass, C Haffner; J Biol Chem. 2010 Aug 20;285(34):26174-81. Epub 2010 Jun 10.
Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
Mitterreiter S, Page RM, Kamp F, Hopson J, Winkler E, Ha HR, Hamid R, Herms J, Mayer TU, Nelson DJ, Steiner H, Stahl T, Zeitschel U, Rossner S, Haass C, Lichtenthaler SF. (2010), J Neurosci. 2010 Jun 30;30(26):8974-83.
The transmembrane protein 147 (TMEM147) is a novel component of the nicalin-nomo protein complex.
Dettmer U, Kuhn PH, Abou-Ajram C, Lichtenthaler SF, Krueger M, Kremmer E, Haass C, Haffner C. (2010), J Biol Chem. 2010 Aug 20;285(34):26174-81. Epub 2010 Jun 10.
Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface its increased processing through the beta-secretase pathway.
Malnar M, Kosicek M, Mitterreiter S, Omerbasic D, Lichtenthaler SF, Goate A, Hecimovic S. (2010), Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):682-91. Epub 2010 May 20.
The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression and Secretion of the Amyloid Precursor Protein.
Ullrich S, Münch A, Neumann S, Kremmer E, Tatzelt J and Lichtenthaler SF. (2010), J Biol Chem. 2010 Jul 2;285(27):20664-74. Epub 2010 Apr 28.
Expression of the anti-amyloidogenic secretase ADAM10 is suppressed by its 5'-untranslated region.
Lammich S, Buell D, Zilow S, Ludwig AK, Nuscher B, Lichtenthaler SF, Prinzen C, Fahrenholz F, Haass C. (2010), J Biol Chem. 2010 May 21;285(21):15753-60. Epub 2010 Mar 26.
Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis
O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hébert SS, De Strooper B, Haass C, Bennett DA, Vassar R, Neuron. 2008 Dec 26;60(6):988-1009.
The novel sorting nexin SNX33 interferes with cellular PrPSc formation by modulation of PrPc shedding
Heiseke A, Schöbel S, Lichtenthaler SF, Vorberg I, Groschup MH, Kretzschmar H, Schätzl HM, Nunziante M, Traffic. 2008 Jul;9(7):1116-29. Epub 2008 Apr 18.
A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein
Schöbel S, Neumann S, Hertweck M, Dislich B, Kuhn PH, Kremmer E, Seed B, Baumeister R, Haass C, Lichtenthaler SF, J Biol Chem. 2008 May 23;283(21):14257-68. Epub 2008 Mar 19.
Nonsteroidal Anti-Inflammatory Drugs and Ectodomain Shedding of the Amyloid Precursor Protein
Leuchtenberger S, Maler J, Czirr E, Ness J, Lichtenthaler SF, Esselmann H, Pietrzik CU, Wiltfang J, Weggen S, Neurodegener Dis. 2008 Mar 18 [Epub ahead of print]