Magdalini Polymenidou | University of Zurich, Switzerland (original) (raw)

Papers by Magdalini Polymenidou

Proceedings of the National Academy of Sciences of the United States of America, Jan 5, 2004

Prion diseases are characterized by the deposition of an abnormal form (termed PrP(Sc)) of the ce... more Prion diseases are characterized by the deposition of an abnormal form (termed PrP(Sc)) of the cellular prion protein (PrP(C)). Because antibodies to PrP(C) can antagonize deposition of PrP(Sc) in cultured cells and mice, they may be useful for anti-prion therapy. However, induction of protective anti-prion immune responses in WT animals may be hindered by host tolerance. Here, we studied the cellular and molecular basis of tolerance to PrP(C). Immunization of Prnp(o/o) mice with bacterially expressed PrP (PrP(REC)) resulted in vigorous humoral immune responses to PrP(REC) and native cell-surface PrP(C). Instead, WT mice yielded antibodies that failed to recognize native PrP(C) despite immunoreactivity with PrP(REC), even after immunization with PrP-PrP polyprotein and/or upon administration of anti-OX40 antibodies. Consequently, immunized WT mice experienced insignificantly delayed prion pathogenesis upon peripheral prion challenge. Anti-PrP immune responses in Prnp(o/o) mice were ...

RNA processing regulation in neuronal integrity. However, a comprehensive protein-RNA interaction... more RNA processing regulation in neuronal integrity. However, a comprehensive protein-RNA interaction map for TDP-43 and identification of post-transcriptional events that may be crucial for neuronal survival remain to be established.

Brain pathology (Zurich, Switzerland), 2011

Protease-resistant prion protein (PrP(Sc) ) is diagnostic of prion disease, yet its detection is ... more Protease-resistant prion protein (PrP(Sc) ) is diagnostic of prion disease, yet its detection is frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical familial prion disease. Brain PrP(Sc) was undetectable by conventional Western blotting and barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern suggestive of noncanonical conformation. Therefore, we used a novel misfolded protein assay (MPA) that detects PrP aggregates independently of their protease resistance. The MPA revealed the presence of aggregated PrP in similar amounts as in typical sporadic Creutzfeldt-Jakob disease. These findings suggest that measurements of PrP aggregation with the MPA may be potentially more sensitive than protease-based methodologies.

With the epizootics of bovine spongiform encephalopathy (BSE) in North American cattle, BSE infec... more With the epizootics of bovine spongiform encephalopathy (BSE) in North American cattle, BSE infections in goats, new forms of human Creutzfeldt-Jakob disease (CJD) and the spread of chronic wasting disease in North American deer and elk, one wonders whether we are gaining control over the transmissible spongiform encephalopathies (TSEs). Although many basic scientific questions in the prion field remain hotly debated and unresolved [1], including the function of the cellular prion protein (PrP), light has been shed on a diverse array of topics, and discussions at the latest TSE meeting ranged broadly from yeast prion fibril assembly to mammalian prion neurotoxicity to future TSE therapies. Prion diseases are protein misfolding disorders which cause degeneration of the central nervous system (CNS) and ultimately death. The unique and surprising feature is that prion diseases are infectious. Yeast prions are derived from proteins differing from the mammalian PrP but are also infectious, self propagating proteins which typically can convert into an aggregated, amyloidogenic form having high beta sheet content. The simple yeast organism has served as a valuable model for understanding aspects of prion biology, such as prion fibril assembly.

Prion diseases are neurodegenerative diseases characterized by the conversion of the cellular pri... more Prion diseases are neurodegenerative diseases characterized by the conversion of the cellular prion protein PrP(c) into a pathogenic isoform PrP(sc). Passive immunization with antiprion monoclonal antibodies can arrest the progression of prion diseases. Here, the crystal structure of the Fab fragment of an antiprion monoclonal antibody, POM1, in complex with human prion protein (huPrP(c)) has been determined to 2.4 Å resolution. The prion epitope of POM1 is in close proximity to the epitope recognized by the purportedly therapeutic antibody fragment ICSM18 Fab in complex with huPrP(c). POM1 Fab forms a 1:1 complex with huPrP(c) and the measured K(d) of 4.5 × 10(-7) M reveals moderately strong binding between them. Structural comparisons have been made among three prion-antibody complexes: POM1 Fab-huPrP(c), ICSM18 Fab-huPrP(c) and VRQ14 Fab-ovPrP(c). The prion epitopes recognized by ICSM18 Fab and VRQ14 Fab are adjacent to a prion glycosylation site, indicating possible steric hindrance and/or an altered binding mode to the glycosylated prion protein in vivo. However, both of the glycosylation sites on huPrP(c) are positioned away from the POM1 Fab binding epitope; thus, the binding mode observed in this crystal structure and the binding affinity measured for this antibody are most likely to be the same as those for the native prion protein in vivo.

PLOS One, 2008

Not Available Bibtex entry for this abstract Preferred format for this abstract (see Preferences)... more Not Available Bibtex entry for this abstract Preferred format for this abstract (see Preferences) Find Similar Abstracts: Use: Authors Title Return: Query Results Return items starting with number Query Form Database: Astronomy Physics arXiv e-prints

Nature Reviews Molecular Cell Biology, 2007

Nature Neuroscience, 2009

The prion protein PrP C is infamous for its role in disease, yet its normal physiological functio... more The prion protein PrP C is infamous for its role in disease, yet its normal physiological function remains unknown. Here we report a novel behavioral phenotype of PrP −/− mice in an odor-guided task. This phenotype is manifest in three PrP knockout lines on different genetic backgrounds, strong evidence it is specific to the lack of PrP C rather than other genetic factors. PrP −/− mice also display altered behavior in a second olfactory task, suggesting the phenotype is olfactory specific. Furthermore, PrP C deficiency affects oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Importantly, both the behavioral and electrophysiological alterations found in PrP −/− mice are rescued by transgenic neuronal-specific expression of PrP C . These data suggest a critical role for PrP C in the normal processing of sensory information by the olfactory system.

$Research paper thumbnail of Canine MDCK cell lines are refractory to infection with human and mouse prions$

Proceedings of the National Academy of Sciences, 2004

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, a... more DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ.

Proceedings of the National Academy of Sciences, 2013

Transactivating response region DNA binding protein (TDP-43) is the major protein component of ub... more Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

PLoS ONE, 2009

Background: A key event in transmissible spongiform encephalopathies (TSEs) is the conversion of ... more Background: A key event in transmissible spongiform encephalopathies (TSEs) is the conversion of the soluble, proteasesensitive glycosylated prion protein (PrP C ) to an abnormally structured, aggregated and partially protease-resistant isoform (PrP Sc ). Both PrP isoforms bear two potential glycosylation sites and thus in a typical western blot with an anti-PrP antibody three distinct bands appear, corresponding to the di-, mono-or unglycosylated forms of the protein. The relative intensity and electrophoretic mobility of the three bands are characteristic of each TSE strain and have been used to discriminate between them.

PLoS ONE, 2008

PrP Sc , a misfolded and aggregated form of the cellular prion protein PrP C , is the only define... more PrP Sc , a misfolded and aggregated form of the cellular prion protein PrP C , is the only defined constituent of the transmissible agent causing prion diseases. Expression of PrP C in the host organism is necessary for prion replication and for prion neurotoxicity. Understanding prion diseases necessitates detailed structural insights into PrP C and PrP Sc . Towards this goal, we have developed a comprehensive collection of monoclonal antibodies denoted POM1 to POM19 and directed against many different epitopes of mouse PrP C . Three epitopes are located within the N-terminal octarepeat region, one is situated within the central unstructured region, and four epitopes are discontinuous within the globular C-proximal domain of PrP C . Some of these antibodies recognize epitopes that are resilient to protease digestion in PrP Sc . Other antibodies immunoprecipitate PrP C , but not PrP Sc . A third group was found to immunoprecipitate both PrP isoforms. Some of the latter antibodies could be blocked with epitope-mimicking peptides, and incubation with an excess of these peptides allowed for immunochromatography of PrP C and PrP Sc . Amino-proximal antibodies were found to react with repetitive PrP C epitopes, thereby vastly increasing their avidity. We have also created functional single-chain miniantibodies from selected POMs, which retained the binding characteristics despite their low molecular mass. The POM collection, thus, represents a unique set of reagents allowing for studies with a variety of techniques, including western blotting, ELISA, immunoprecipitation, conformation-dependent immunoassays, and plasmon surface plasmon resonance-based assays.

Nature Neuroscience, 2011

Nature Neuroscience, 2012

nature neurOSCIenCe advance online publication a r t I C l e S RESULTS RNA targets of FUS/TLS in ... more nature neurOSCIenCe advance online publication a r t I C l e S RESULTS RNA targets of FUS/TLS in mouse and human brain FUS/TLS protein-RNA complexes cross-linked in vivo by ultraviolet light were efficiently immunoprecipitated using antibodies to three ,3,8 FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.