A5027400726- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Trace Elements in Health
- RNA regulation and disease
- Monoclonal and Polyclonal Antibodies Research
- HIV Research and Treatment
- Hereditary Neurological Disorders
- CRISPR and Genetic Engineering
- Nuclear Receptors and Signaling
- Biochemical and Structural Characterization
- RNA Research and Splicing
- Diabetes Treatment and Management
- Alzheimer's disease research and treatments
- Alcoholism and Thiamine Deficiency
- Urban Planning and Valuation
- Receptor Mechanisms and Signaling
- 3D Surveying and Cultural Heritage
- Olfactory and Sensory Function Studies
- Pulmonary Hypertension Research and Treatments
- Infectious Encephalopathies and Encephalitis
- Protease and Inhibitor Mechanisms
- Neuroscience and Neuropharmacology Research
- Viral Infections and Immunology Research
- Cultural Heritage Management and Preservation
- Neuroinflammation and Neurodegeneration Mechanisms
University Hospital of Zurich
2016-2022
University of Zurich
2016-2022
University College London
2013
Dulbecco Telethon Institute
2008-2013
Mario Negri Institute for Pharmacological Research
2008-2012
Although prion infections cause cognitive impairment and neuronal death, transcriptional translational profiling shows progressive derangement within glia but surprisingly little changes neurons. Here we expressed PrPC selectively in neurons astrocytes of mice. After infection, both astrocyte neuron-restricted expression led to copious brain accumulation PrPSc . As expected, was associated with typical disease. However, mice astrocyte-restricted experienced a normal life span, did not...
SummaryHow mutant prion protein (PrP) leads to neurological dysfunction in genetic diseases is unknown. Tg(PG14) mice synthesize a misfolded PrP which partially retained the neuronal endoplasmic reticulum (ER). As these age, they develop ataxia and massive degeneration of cerebellar granule neurons (CGNs). Here, we report that motor behavioral deficits emerge before neurodegeneration are associated with defective glutamate exocytosis from due impaired calcium dynamics. We found interacts...
Abstract Prion infections cause conformational changes of the cellular prion protein (PrP C ) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering flexibility α2–α3 β2–α2 loops PrP . Expression a 2Cys mutant mimicking H-latch was constitutively whereas R207A unable form conferred resistance infection. High-affinity prevented induction repressed prion-related neurodegeneration in...
Growing evidence suggests that a physiological activity of the cellular prion protein (PrP C ) plays crucial role in several neurodegenerative disorders, including and Alzheimer's diseases. However, how functional PrP is subverted to deliver neurotoxic signals remains uncertain. Transgenic (Tg) mice expressing with deletion residues 105–125 central region (referred as ΔCR PrP) provide important insights into this problem. Tg(ΔCR) exhibit neonatal lethality massive degeneration cerebellar...
Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting existence deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 mGluR5) can form complexes with (PrPC), we investigated impact mGluR1 mGluR5 inhibition on toxicity ex vivo in vivo. We found that pharmacological antagonized dose-dependently neurotoxicity triggered by...
Abstract The key event in the pathogenesis of prion diseases is conformational conversion normal protein (PrP) (PrP C ) into an infectious, aggregated isoform Sc that has a high content β‐sheet. Historically, great deal effort been devoted to developing antibodies specifically recognize PrP but not , as such would have enormous diagnostic and experimental value. A mouse monoclonal IgM antibody (designated 15B3) three motif‐grafted (referred IgG 19–33, 89–112, 136–158) previously reported...
Prions are transmissible agents causing lethal neurodegenerative diseases that composed of aggregates misfolded cellular prion protein (PrPSc). Despite non-fibrillar oligomers having been proposed as the most infectious particles, prions purified from diseased brains usually consist large and fibrillar PrPSc aggregates, whose protease-resistant core (PrPres) encompasses whole C-terminus PrP. In contrast, Gerstmann-Sträussler-Scheinker disease associated with alanine to valine substitution at...
Prions are the infectious agents causing transmissible spongiform encephalopathies (TSE), progressive, inexorably lethal neurological diseases. Antibodies targeting globular domain (GD) of cellular prion protein PrPC trigger a neurotoxic syndrome morphologically and molecularly similar to disease. This phenomenon raises question whether such antibodies induce prions de novo. Here we exposed cerebellar organotypic cultured slices (COCS) antibody, POM1. We then inoculated COCS homogenates into...
Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP-binding in a synthetic human Fab phage display library, 49 of which characterized detail. Antibodies directed the flexible tail conferred neuroprotection infectious prions. We then mined published repertoires circulating B cells from healthy humans and found similar to protective phage-derived antibodies. When expressed recombinantly, these exhibited...
Bovine spongiform encephalopathy (BSE) is a prion disease of cattle that caused by the misfolding cellular protein (PrP C ) into an infectious conformation Sc ). PrP predominantly α-helical membrane misfolds β-sheet rich, state, which has high propensity to self-assemble amyloid fibrils. Three strains BSE prions can cause in cattle, including classical (C-type) and two atypical strains, named L-type H-type BSE. To date, there no detailed information available about structure any strains. In...
It has been shown recently that PrP (prion protein) and the calcium channel auxiliary α2δ subunits interact in neurons expression systems [Senatore, Colleoni, Verderio, Restelli, Morini, Condliffe, Bertani, Mantovani, Canovi, Micotti, Forloni, Dolphin, Matteoli, Gobbi Chiesa (2012) Neuron 74, 300-313]. In present study we examined whether there was an effect of on currents. We have when is co-expressed with channels formed from CaV2.1/β α2δ-1 or α2δ-2, a consistent decrease current density....
The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. prion protein (PrP) a potent activator could be used as potential therapeutic agent treating demyelinating dysmyelinating diseases. We designed dimeric Fc-fusion comprising myelinotrophic domain PrP (FT 2 Fc), which activated vitro exhibited favorable pharmacokinetic properties for vivo treatment neuropathies. While chronic FT Fc...
Abstract Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here we identified >6000 PrP-binding in a synthetic human Fab phage display library, 49 of which characterized detail. Antibodies directed the flexible tail conferred neuroprotection infectious prions. We then mined published repertoires circulating B cells from healthy humans and found similar to protective phage-derived antibodies. When expressed recombinantly, these...
Abstract Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical dissection and hypertension. Although these represent significant risk factors or comorbidities ischemic stroke, role in brain small vessel disease stroke most important survival mechanism, such the recruitment of collateral arteries like posterior communicating (PcomAs), remains unknown....
Although prion infections cause cognitive impairment and neuronal death, transcriptional translational profiling shows progressive derangement within glia but surprisingly little changes neurons. Here we expressed PrP C selectively in neurons, astrocytes or oligodendrocytes of mice. After infection, both astrocyte neuron-restricted expression led to copious brain accumulation Sc . As expected, was associated with typical disease. However, mice astrocyte-restricted experienced a normal life...
Summary Prion infections cause conformational changes of PrP C and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (“H-latch”) altering the flexibility α2-α3 β2-α2 loops . Expression a 2Cys mutant mimicking H-latch was constitutively whereas R207A unable form conferred resistance prion infection. High-affinity prevented induction repressed prion-related neurodegeneration in organotypic cerebellar...
Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic pharmacological perturbations have hindered use of mammals dissecting aging-regulatory molecular networks discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics process mammalian using cultured mouse slices. Genome-wide gene expression analyses showed slices spontaneously upregulated...
Abstract The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. prion protein (PrP) a potent activator could be used as potential therapeutic agent treating demyelinating dysmyelinating diseases. We designed dimeric Fc-fusion comprising myelinotrophic domain PrP (FT 2 Fc), which activated vitro exhibited favorable pharmacokinetic properties for vivo treatment neuropathies. While chronic...