MDC Lab Coats

Prof. Dr. Thomas Willnow

Molecular Physiology

Max Delbrück Center for Molecular Medicine (MDC)

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Research interest:

Our main research interest is in the area of molecular and cellular physiology. Particularly, we focus on the functional characterization of orphan endocytic and signaling receptors in the nervous system and their relevance for normal neuronal function as well as neurodegenerative processes. Recently, we demonstrated that megalin, a member of the LDL receptor gene family acts as endocytic receptor for steroid hormones and that it plays a central role in embryonic development of the forebrain. We also characterized SORLA and sortilin, members of a novel class of endocytic receptors in neurons. We showed that SORLA regulates intracellular transport and processing of the amyloid precursor protein, the etiologic agent in Alzheimer’s disease, and that this receptor represents a major risk factor for the late-onset form of the disease. Concerning sortilin, we elucidated its role as receptor for pro-nerve growth factor, responsible for induction of cell death during acute or chronic distress of the nervous system.

Methods:

Generation and analysis of transgenic mouse models (immunohistological, physiological and behavioral studies), cell biology (confocal microscopy, life cell imaging, FRET, uptake studies), biochemistry (BIAcore, protein interaction studies)

Selected publications:

Jansen P, Giehl K, Nyengaard JR, Teng K, Lioubinski O, Sjoegaard SS, Breiderhoff T, Gotthardt M, Lin F, Eilers A, Petersen CM, Lewin GR, Hempstead BL, Willnow TE*, Nykjaer A* (2007) Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci 10:1449-1457. * equal corresponding authorship

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168-177.

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102:13461-13466.

Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE (2005) Role of endocytosis in cellular uptake of sex steroids. Cell 122:751-762.

Spoelgen R, Hammes A, Anzenberger U, Zechner D, Andersen OM, Jerchow B, Willnow TE (2005) LRP2/megalin is required for patterning of the ventral telencephalon. Development 132:405-414.

Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843-848.

Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96:507-515.