Research Report 2010 - MDC

Previously, we demonstrated that sortilin is an essentialcomponent for transmitting proNGF-induced deathsignals through p75 NTR (Fig. 2B). In this death receptorcomplex, sortilin specifically binds the pro-domain ofthe proneurotrophins with high affinity while p75 NTRsimultaneously engages the mature NGF domain. Theformation of this ternary receptor-ligand complex iscrucial for the pro-apoptotic function. In this model,sortilin acts as the crucial molecular switch thatenables neurons coexpressing p75 NTR and Trk receptorsto selectively respond to proNGF by apoptosis ratherthan survival (Fig. 2B).Now, we further substantiated the role of sortilin inproNT mediated cell death by generating a sortilin-deficientmouse model and by testing the contribution ofthe p75 NTR /sortilin receptor complex to neuronal viabilityin vivo. In the developing retina, sortilin -/- mice exhibitreduced neuronal apoptosis indistinguishable fromthat observed in p75 NTR-/- . Surprisingly, while sortilin deficiencydoes not impact on developmentally regulatedapoptosis of sympathetic neurons, it prevents their agedependentdegeneration. Furthermore, in an injury paradigmlesioned corticospinal neurons in sortilin -/- miceare protected from death. Thus, the sortilin pathwayplays distinct roles in proNT-induced apoptotic signalingin pathological conditions but also in specific stagesof neuronal development and ageing.Selected PublicationsNykjaer, A, Lee, R, Teng, TT, Nielsen, MS, Jansen, P, Madsen, P, Jacobsen, C,Kliemannel, M, Willnow, TE, Hempstead, B and Petersen, CM. (2004). Anovel neurotrophin receptor essential for proNGF induced neuronal celldeath. Nature 427, 843-848.Andersen, OM, Reiche, R, Schmidt, V, Gotthardt, M, Spoelgen, R, Behlke, J,von Arnim, CAF, Breiderhoff, T, Jansen, P, Wu, X, Bales, KR, Cappai, R,Masters, CL, Gliemann, J, Mufson, EJ, Hyman, BT, Paul, SM, Nykjær, N andWillnow, TE. (2005) SorLA/LR11, a neuronal sorting receptor that regulatesprocessing of the amyloid precursor protein. Proc. Natl. Acad. Sci. USA 102,13461-13466.Hammes, A, Andreassen, TK, Spoelgen, R, Raila, J, Huebner, N, Schulz, H,Metzger, J, Schweigert, FJ, Luppa, PB, Nykjaer*, A. and Willnow*, TE. (2005)Impaired development of the reproductive organs in mice lackingmegalin, an endocytic receptor for steroid hormones. Cell 122, 751-62.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* and Nykjaer, A*. (2007) Roles for thepro-neurotrophin receptor sortilin in neuronal development, aging andbrain injury. Nature Neuroscience 10, 1449-57.Willnow*, TE, Petersen, CM and Nykjaer*, A. (2008). VPS10P domainreceptors – regulators of neuronal viability and function. Nature ReviewsNeuroscience 9, 899-909.* joint corresponding authorshipPerspectiveDysregulation of vesicular protein transport is emergingas a molecular mechanism of major importanceunderlying many disease processes. Obviously, intracellularsorting receptors of the VPS10P domain receptorgene family play key roles in these processes. Our futurework has yet to refine the molecular details how sortilinand SORLA affect neuronal viability and functionthrough their interactions with neurotrophin receptorsand APP. Furthermore, novel activities of the neuronalprotein transport machinery may be uncovered as welearn more about the orphan receptors SORCS1,SORCS2, and SORCS3. As well as in the nervous system,SORLA and sortilin are also distinctly expressed in nonneuronalcell types such as in kidney, liver and adiposetissue. Our preliminary studies have uncovered importantroles played by these receptors in renal ion transportand blood pressure regulation (SORLA) or in controlof systemic cholesterol homeostasis (sortilin). In thefuture, we expect to gain novel insights into proteinsorting pathways that may be central to the developmentof renal and metabolic disorders.Cardiovascular and Metabolic Disease Research 9