Cooperation Unit Biochemistry of γ-Secretase
Prof. Dr. Harald Steiner
Cooperation Unit Leader
Prof. Steiner is group leader at the Biomedical Center Munich at the LMU Munich
Feodor-Lynen-Str. 17
81377 München

harald.steiner@dzne.de
 +49 89 4400-46535

Areas of investigation/research focus

Accumulation of the amyloid-β peptide (Aβ) in senile plaques is an invariable pathological hallmark of Alzheimer´s disease (AD). Aβ is derived by proteolytic processing of the β-amyloid precursor protein (APP) through the combined action of the membrane bound aspartyl proteases β-secretase and γ-secretase. γ-Secretase is a large protein complex composed of the AD-associated presenilin (PS) proteins as catalytic subunit, nicastrin (NCT), APH-1 and PEN-2 and cleaves APP within its transmembrane domain. To allow a better understanding of the mode of action of γ-secretase and of intramembrane proteolysis in general research our group currently focuses on following aspects of γ-secretase biochemistry:

  1. Molecular recognition of γ-secretase substrates
  2. Modulation of γ-secretase activity

 

Key Publications

Akio Fukumori, Harald Steiner. Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO Journal. 2016 Jul 31; 35:1628-1643. doi: 10.15252/embj.201694151
Benedikt Kretner, Johannes Trambauer, Akio Fukumori, Janina Mielke, Peer-Hendrik Kuhn, Elisabeth Kremmer, Armin Giese, Stefan F Lichtenthaler, Christian Haass, Thomas Arzberger, Harald Steiner. Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease. EMBO Molecular Medicine. 2016 Apr 30; 8:458-465. doi: 10.15252/emmm.201505952
Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of γ-secretase activity. Nat Cell Biol. 2003 Jan 01; 5:486-8. doi: 10.1038/ncb960
Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, …, Steiner H. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production. Proc Natl Acad Sci U S A. 2002 Jan 01; 99:8025-30. doi: 10.1073/pnas.112686799
Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy J, Capell A, Meyn L, Grim ML, Baumeister R, Fechteler K, Haass C. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol. 2000 Nov 01; 2:848-51. doi: 10.1038/35041097

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