Thomas E Willnow

Max-Delbrück-Centrum für Molekulare Medizin, Berlín, Berlin, Germany

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Publications (147)1102.58 Total impact

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    ABSTRACT: The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole embryo cultures showed that LRP2 deficient neuroepithelial cells are unable to mediate uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared to control littermates. Moreover, the folic acid dependent gene Alx3 is significantly down regulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure.
    Journal of Cell Science 03/2014; · 5.88 Impact Factor
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    ABSTRACT: SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA's Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.
    Science translational medicine 02/2014; 6(223):223ra20. · 10.76 Impact Factor
  • Vanessa Schmidt, Anne‐Sophie Carlo, Thomas E. Willnow
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    ABSTRACT: Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid-β (Aβ) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aβ from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
    Wiley Interdisciplinary Reviews Systems Biology and Medicine 02/2014; · 3.68 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.
    Acta Neuropathologica 12/2013; · 9.73 Impact Factor
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    ABSTRACT: Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aβ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein (PACS) 1, an adaptor that shuttles proteins between transGolgi network (TGN) and endosomes. Using PACS1 knockdown studies in neuronal cell lines and investigations in transgenic mice expressing a PACS1-binding defective mutant of SORLA, we document that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons, and in increased APP processing in the brain. Loss of PACS1 also impairs proper expression of the cation-independent mannose-6 phosphate receptor and its target cathepsin B, a protease that breaks down Aβ. Thus, our data identified the importance of PACS1-dependent protein sorting for control of amyloidogenic burden via both SORLA-dependent and SORLA-independent mechanisms.
    Molecular and cellular biology 09/2013; · 6.06 Impact Factor
  • Thomas E Willnow, Olav M Andersen
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    ABSTRACT: Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid β peptides (Aβ) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
    Journal of Cell Science 06/2013; · 5.88 Impact Factor
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    ABSTRACT: Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β (Aβ) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
    Journal of Neuroscience 01/2013; 33(1):358-70. · 6.91 Impact Factor
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    ABSTRACT: SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction.
    PLoS ONE 01/2013; 8(9):e75006. · 3.73 Impact Factor
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    ABSTRACT: A growing body of evidence suggests a role for soluble alpha-amyloid precursor protein (sAPPalpha) in pathomechanisms of Alzheimer disease (AD). This cleavage product of APP was identified to have neurotrophic properties. However, it remained enigmatic what proteins, targeted by sAPPalpha, might be involved in such neuroprotective actions. Here, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to analyze proteome changes downstream of sAPPalpha in neurons. We present evidence that sAPPalpha regulates expression and activity of CDK5, a kinase that plays an important role in AD pathology. We also identified the cytoprotective chaperone ORP150 to be induced by sAPPalpha as part of this protective response. Finally, we present functional evidence that the sAPPalpha receptor SORLA is essential to mediate such molecular functions of sAPPalpha in neurons.
    PLoS ONE 01/2013; 8(6):e65920. · 3.73 Impact Factor
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    ABSTRACT: Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington's disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB.
    PLoS ONE 01/2013; 8(8):e72164. · 3.73 Impact Factor
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  • Thomas E Willnow, Annabel Christ, Annette Hammes
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    ABSTRACT: Receptor-mediated endocytosis provides a mechanism by which cells take up signaling molecules from the extracellular space. Recent studies have shown that one class of endocytic receptors, the low-density lipoprotein receptor-related proteins (LRPs), is of particular relevance for embryonic development. In this Primer, we describe how LRPs constitute central pathways that modulate morphogen presentation to target tissues and cellular signal reception, and how LRP dysfunction leads to developmental disturbances in many species.
    Development 12/2012; 139(23):4311-9. · 6.60 Impact Factor
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    ABSTRACT: Immunological control of infections or tumors depends on the release of effector cytokines and polarized secretion of cytotoxic granules from T cells and natural killer cells. Here we show that the sorting receptor Sortilin controlled both processes. In murine Sortilin-deficient cytotoxic T lymphocytes, regulated secretion of granzyme A and cytotoxic killing was enhanced and correlated with increased vesicle-associated membrane protein 7 availability. In contrast, loss of Sortilin reduced the release of interferon-γ upon infections and in autoimmune colitis. Exit of interferon-γ from the Golgi apparatus required the presence of Sortilin. Furthermore, we tracked the transport route of interferon-γ beyond this Sortilin-dependent Golgi to early endosome step. In wild-type T cells, trafficking of interferon-γ from the endosomal sorting platform to the plasma membrane proceeded independently of recycling endosomes, and interferon-γ remained excluded from late endosomes. Our results suggest that Sortilin modulates systemic immune responses through exocytic sorting of immunological effector molecules.
    Immunity 10/2012; · 19.80 Impact Factor
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    ABSTRACT: Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.
    Journal of Alzheimer's disease: JAD 09/2012; · 4.17 Impact Factor
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    ABSTRACT: In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ion transport. In the thick ascending limb (TAL) of Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular and paracellular routes. TAL salt transport maintains the concentrating ability of the kidney and generates a transepithelial voltage that drives the reabsorption of calcium and magnesium. Thus, functionality of TAL ion transport depends strongly on the properties of the paracellular pathway. To elucidate the role of the tight junction protein claudin-10 in TAL function, we generated mice with a deletion of Cldn10 in this segment. We show that claudin-10 determines paracellular sodium permeability, and that its loss leads to hypermagnesemia and nephrocalcinosis. In isolated perfused TAL tubules of claudin-10-deficient mice, paracellular permeability of sodium is decreased, and the relative permeability of calcium and magnesium is increased. Moreover, furosemide-inhibitable transepithelial voltage is increased, leading to a shift from paracellular sodium transport to paracellular hyperabsorption of calcium and magnesium. These data identify claudin-10 as a key factor in control of cation selectivity and transport in the TAL, and deficiency in this pathway as a cause of nephrocalcinosis.
    Proceedings of the National Academy of Sciences 08/2012; 109(35):14241-6. · 9.74 Impact Factor
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    ABSTRACT: BACKGROUND: Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aß peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. RESULTS: In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose-response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of ß-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. CONCLUSIONS: Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and ß-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer's disease.
    BMC Systems Biology 06/2012; 6(1):74. · 2.98 Impact Factor
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    ABSTRACT: To identify SORL1 risk genotypes that determine receptor protein expression in the human brain. DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively. Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank. Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease. Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein. Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.
    Archives of neurology 03/2012; 69(3):373-9. · 7.58 Impact Factor
  • Anders Nykjaer, Thomas E Willnow
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    ABSTRACT: Sortilin is a type-1 receptor expressed in neurons of the central and peripheral nervous systems. Initially considered a rather peculiar receptor resembling an intracellular sorting protein in yeast, sortilin has emerged as a key player in the regulation of neuronal viability and function. It acts as a receptor of neurotrophic factors and neuropeptides, but also as a co-receptor to cytokine receptors, tyrosine receptor kinases, G-protein coupled receptors and ion-channels. Here, we review recent findings that identified multiple roles for sortilin in the cellular transport and signaling. Furthermore, we discuss how sortilin contributes not only to the functional integrity of the nervous system during physiological conditions but also plays an important role during neuronal injury and disease processes.
    Trends in Neurosciences 02/2012; 35(4):261-70. · 13.58 Impact Factor
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    ABSTRACT: Sonic hedgehog (SHH) is a regulator of forebrain development that acts through its receptor, patched 1. However, little is known about cellular mechanisms at neurulation, whereby SHH from the prechordal plate governs specification of the rostral diencephalon ventral midline (RDVM), a major forebrain organizer. We identified LRP2, a member of the LDL receptor gene family, as a component of the SHH signaling machinery in the RDVM. LRP2 acts as an apical SHH-binding protein that sequesters SHH in its target field and controls internalization and cellular trafficking of SHH/patched 1 complexes. Lack of LRP2 in mice and in cephalic explants results in failure to respond to SHH, despite functional expression of patched 1 and smoothened, whereas overexpression of LRP2 variants in cells increases SHH signaling capacity. Our data identify a critical role for LRP2 in SHH signaling and reveal the molecular mechanism underlying forebrain anomalies in mice and patients with Lrp2 defects.
    Developmental cell 02/2012; 22(2):268-78. · 13.36 Impact Factor

Publication Stats

6k Citations
1,102.58 Total Impact Points


  • 1997–2014
    • Max-Delbrück-Centrum für Molekulare Medizin
      • Research Team Molecular Cardiovascular Research
      Berlín, Berlin, Germany
  • 2003–2012
    • Charité Universitätsmedizin Berlin
      • • Institute of Vegetative Anatomy
      • • Department of Pediatrics, Division of Nephrology
      Berlín, Berlin, Germany
  • 1998–2012
    • Aarhus University
      • • Department of Biomedicine
      • • Department of Medical Biochemistry
      • • Institute of Anatomy
      Aars, Region North Jutland, Denmark
  • 2010
    • University of Dundee
      Dundee, Scotland, United Kingdom
  • 2000–2003
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 2002
    • Wroclaw Medical University
      • Faculty of Pharmacy
      Wrocław, Lower Silesian Voivodeship, Poland
  • 1999–2001
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1993–2000
    • University of Texas Southwestern Medical Center
      • Department of Molecular Genetics
      Dallas, TX, United States
  • 1997–1999
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany