Project P6: Role of transmembrane domain interactions for g-secretase substrate recognition using the TREM2/DAP12 complex


This project addresses two central questions of this research unit, namely what are the critical requirements for a substrate to be cleaved within its transmembrane (TM) domain and how do TM domain interactions (i.e. dimerization) influence substrate recognition by γ-secretase and other intramembrane cleaving proteases such as members of the SPP/SPPL family.


To identify such properties, we will use the pathologically highly relevant TREM2/DAP12 interaction as a model system. Sequence variants within TREM2 dramatically increase the risk for Alzheimer's disease and related neurodegenerative disorders. TREM2 - a type-1 transmembrane innate immune receptor - is a substrate for regulated intramembrane proteolysis and forms a heteromeric complex with its signaling partner DAP12.

Publications (FOR 2290)

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.


γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.

Steiner A, Schlepckow K, Brunner B, Steiner H, Haass C, Hagn F.

EMBO J. 2020 Aug 24:e104247. doi: 10.15252/embj.2019104247. Online ahead of print. PMID: 32830336

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.

Vöglein J, Paumier K, Jucker M, Preische O, McDade E, Hassenstab J, Benzinger TL, Noble JM, Berman SB, Graff-Radford NR, Ghetti B, Farlow MR, Chhatwal J, Salloway S, Xiong C, Karch CM, Cairns N, Mori H, Schofield PR, Masters CL, Goate A, Buckles V, Fox N, Rossor M, Chrem P, Allegri R, Ringman JM, Höglinger G, Steiner H, Dieterich M, Haass C, Laske C, Morris JC, Bateman RJ, Danek A, Levin J; Dominantly Inherited Alzheimer Network. Brain. 2019 May 1;142(5):1429-1440. doi: 10.1093/brain/awz050.


Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C.

Nat Neurosci. 2019 Feb;22(2):191-204. doi: 10.1038/s41593-018-0296-9. Epub 2019 Jan 7. PMID: 30617257


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.



The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism.

Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deußing M, Suárez-Calvet M, Mazaheri F, Parhizkar S, Pettkus N, Wurst W, Feederle R, Bartenstein P, Mueggler T, Arzberger T, Knuesel I, Rominger A, Haass C.

EMBO J. 2017 Jul 3;36(13):1837-1853. doi: 10.15252/embj.201796516. Epub 2017 May 30. PMID: 285594



"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.



Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases.

Fleck D, Voss M, Brankatschk B, Giudici C, Hampel H, Schwenk B, Edbauer D, Fukumori A, Steiner H, Kremmer E, Haug-Kröper M, Rossner MJ, Fluhrer R, Willem M, Haass C.

J Biol Chem. 2016 Jan 1;291(1):318-33. doi: 10.1074/jbc.M115.697995. Epub 2015 Nov 16. PMID: 26574544 Free PMC Article


Publications FOR 2290 PI's

Research Unit FOR 2290