ORCID Profile
0000-0002-0344-6708
Current Organisation
University of Zurich
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Publisher: Wiley
Date: 27-07-2006
Abstract: Interaction of lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTbeta on different lymphocyte subsets to determine how the LTbeta-dependent lymphoid structure influences immune reactivity. All conditionally LTbeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTbeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTbeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTbeta expression influences immune reactivity at two distinct levels: (i) Expression of LTbeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTbeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.
Publisher: Oxford University Press (OUP)
Date: 13-09-2004
DOI: 10.1093/BRAIN/AWH249
Publisher: Proceedings of the National Academy of Sciences
Date: 04-08-2009
Abstract: Despite the importance of the aberrant polymerization of Aβ in the early pathogenic cascade of Alzheimer's disease, little is known about the induction of Aβ aggregation in vivo. Here we show that induction of cerebral β-amyloidosis can be achieved in many different brain areas of APP23 transgenic mice through the injection of dilute Aβ-containing brain extracts. Once the amyloidogenic process has been exogenously induced, the nature of the induced Aβ-deposition is determined by the brain region of the host. Because these observations are reminiscent of a prion-like mechanism, we then investigated whether cerebral β-amyloidosis also can be induced by peripheral and systemic inoculations or by the intracerebral implantation of stainless steel wires previously coated with minute amounts of Aβ-containing brain extract. Results reveal that oral, intravenous, intraocular, and intranasal inoculations yielded no detectable induction of cerebral β-amyloidosis in APP23 transgenic mice. In contrast, transmission of cerebral β-amyloidosis through the Aβ-contaminated steel wires was demonstrated. Notably, plasma sterilization, but not boiling of the wires before implantation, prevented the induction of β-amyloidosis. Our results suggest that minute amounts of Aβ-containing brain material in direct contact with the CNS can induce cerebral β-amyloidosis, but that systemic cellular mechanisms of prion uptake and transport to the CNS may not apply to Aβ.
Publisher: Wiley
Date: 15-02-2007
DOI: 10.1002/JNR.21215
Abstract: Normal physiologic functions of the cellular prion protein (PrPc) are still elusive. This GPI-anchored protein exerts many functions, including roles in neuron proliferation, neuroprotection or redox homeostasis. There are, however, conflicting data concerning its role in synaptic transmission. Although several studies report that PrPc participates in NMDA-mediated neurotransmission, parallel studies describe normal behavior of PrPc-mutant mice. Abnormal axon connections have been described in the dentate gyrus of the hippoc i of PrPc-deficient mice similar to those observed in epilepsy. A study indicates increased susceptibility to kainate (KA) in these mutant mice. We extend the observation of these studies by means of several histologic and biochemical analyses of KA-treated mice. PrPc-deficient mice showed increased sensitivity to KA-induced seizures in vivo and in vitro in organotypic slices. In addition, we show that this sensitivity is cell-specific because interference experiments to abolish PrPc expression increased susceptibility to KA in PrPc-expressing cells. We indicate a correlation of susceptibility to KA in cells lacking PrPc with the differential expression of GluR6 and GluR7 KA receptor subunits using real-time RT-PCR methods. These results indicate that PrPc exerts a neuroprotective role against KA-induced neurotoxicity, probably by regulating the expression of KA receptor subunits.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.11.21265915
Abstract: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898). The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 × 10 −7 , odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 × 10 −6 , OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 × 10 −6 , OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 × 10 −5 . The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
Publisher: Life Science Alliance, LLC
Date: 23-06-2020
Abstract: HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of these B cells with the same molecular profile as in autologous CD4 + T cells. In addition, we established a humanized mouse model to investigate the in vivo interactions of EBV and HIV-1 upon coinfection. The respective mice that reconstitute human immune system components upon transplantation with CD34 + human hematopoietic progenitor cells could recapitulate aspects of EBV and HIV immunobiology observed in dual-infected patients. Upon coinfection of humanized mice, EBV/HIV dual-infected B cells could be detected, but were susceptible to CD8 + T-cell–mediated immune control.
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2022
DOI: 10.1101/2022.05.25.493370
Abstract: Arrayed CRISPR libraries extend the scope of gene-perturbation screens but require large numbers of efficacious sgRNA-expressing vectors. Using a newly invented liquid-phase plasmid cloning methodology, we constructed genome-wide arrayed libraries for human gene ablation (19,936 plasmids), activation, and epigenetic silencing (22,442 plasmids). At least 76% of each plasmid preparation encoded an intact array of 4 non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. We achieved perturbation efficacies of 75-99%, 76-92% and up to 10,000x in deletion, silencing and activation experiments, respectively. Upon conversion into massively parallel lentiviral vectors, an arrayed activation screen of 1,634 human transcription factors yielded 11 novel regulators of the cellular prion protein PrP C . Furthermore, a screen using a pooled version of the ablation library identified 5 novel modifiers of autophagy that went undetected with either of two 1sgRNA libraries. The CRISPR libraries described here represent a powerful resource for the targeted perturbation of human protein-coding genes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-05-2000
DOI: 10.1126/SCIENCE.288.5469.1257
Abstract: In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells (FDCs). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-α/β. Treatment of mice with soluble lymphotoxin-β receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NI.2913
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.NBD.2008.02.001
Abstract: Alzheimer's disease and prion diseases (e.g., Creutzfeldt-Jakob disease) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. However, the intracellular events in prion diseases and their relation with the processing of the amyloid precursor protein (APP) and beta-amyloid generation are unknown. The adaptor protein Dab1 may regulate intracellular trafficking and secretase-mediated proteolysis in APP processing. However, a putative relationship between prion diseases and Dab1/APP interactions is lacking. Thus, we examined, in inoculated animals, whether Dab1 and APP processing are targets of the intracellular events triggered by extracellular exposure to PrP(106-126) peptide. Our in vitro results indicate that PrP(106-126) peptide induces tyrosine phosphorylation of Dab1 by activated members of the Src family of tyrosine kinases (SFK), which implies further Dab1 degradation. We also corroborate these results in Dab1 protein levels in prion-inoculated hamsters. Finally, we show that fibrillar prion peptides have a dual effect on APP processing and beta-amyloid production. First, they block APP trafficking at the cell membrane, thus decreasing beta-amyloid production. In parallel, they reduce Dab1 levels, which also alter APP processing. Lastly, neuronal cultures from Dab1-deficient mice showed severe impairment of APP processing with reduced sAPP secretion and A beta production after prion peptide incubation. Taken together, these data indicate a link between intracellular events induced by exposure to extracellular fibrillar peptide or PrP(res), and APP processing and implicate Dab1 in this link.
Publisher: Proceedings of the National Academy of Sciences
Date: 07-06-1994
Abstract: The cAMP response element binding protein (CREB) has been implicated as a key regulator in the transcriptional control of many genes. To assess the functional importance of CREB in vivo and its role in development, we used gene targeting to generate mice with a disruption of the CREB gene. Homozygous mutant mice appeared healthy and exhibited no impairment of growth or development. In this report we demonstrate that CREB and two other members of the CREB/ATF family, cAMP response element modulation protein (CREM) and activating transcription factor 1 (ATF1), appear to form a unique subgroup within this extensive class of transcription factors. Examination of CREM mRNA and protein levels in CREB mutant mice demonstrated overexpression of CREM in all tissues examined, but no change in ATF1 levels. These data demonstrate that CREB is not the sole mediator of cAMP-dependent transcriptional regulation and probably acts in concert with a specific subset of cAMP response element-binding proteins to transduce the cAMP signal and, in its absence, these same proteins can compensate for CREB function in vivo.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2021
DOI: 10.1101/2021.12.08.471089
Abstract: Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating these age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies 1,2 , which involve human-specific mechanisms 3–6 that cannot be directly studied in animal models. To explore the emergence and consequences of TDP-43 pathologies, we generated iPSC-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors 7 . Single-cell transcriptomics (scRNA-seq) and comparison to independent NSCs 8 , showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks. Neuronal and glial maturation in iCoMoNSC-derived cultures was similar to that of cortical organoids 9 . Overexpression of wild-type TDP-43 in a minority of iCoMoNSC-derived neurons led to progressive fragmentation and aggregation, resulting in loss of function and neurotoxicity. scRNA-seq revealed a novel set of misregulated RNA targets coinciding in both TDP-43 overexpressing neurons and patient brains exhibiting loss of nuclear TDP-43. The strongest misregulated target encoded for the synaptic protein NPTX2, which was consistently misaccumulated in ALS and FTLD patient neurons with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby highlighting a new pathway of neurotoxicity.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.JMB.2004.10.088
Abstract: Soluble dimeric prion protein (PrP-Fc(2)) binds to the disease-associated prion protein PrP(Sc), and inhibits prion replication when expressed in transgenic mice. Prion inhibition is effective even if PrP-Fc(2) is expressed at low levels, suggesting that its affinity for PrP(Sc) is higher than that of monomeric PrP(C). Here, we model prion accumulation as an exponential replication cycle of prion elongation and breakage. The exponential growth rate corresponding to this cycle is reflected in the incubation period of the disease. We use a mathematical model to calculate the exponential growth rate, and fit the model to in vivo data on prion incubation times corresponding to different levels of PrP(C) and PrP-Fc(2). We find an excellent fit of the model to the data. Surprisingly, targeting of PrP(Sc) can be effective at concentrations of PrP-Fc(2) lower than that of PrP(C), even if PrP-Fc(2) and PrP(C) have the same affinity for PrP(Sc). The best fit of our model to data predicts that the replicative prion consists of PrP(Sc) oligomers with a mean size of four to 15 units.
No related grants have been discovered for Adriano Aguzzi.