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Dive into the research topics where Emiliano Biasini is active.

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Featured researches published by Emiliano Biasini.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein

Claudia Balducci; Marten Beeg; Matteo Stravalaci; Antonio Bastone; Alessandra Sclip; Emiliano Biasini; Laura Colombo; Claudia Manzoni; Tiziana Borsello; Roberto Chiesa; Marco Gobbi; Mario Salmona; Gianluigi Forloni

Inability to form new memories is an early clinical sign of Alzheimer’s disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ1–42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ1–42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrPC) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ1–42 oligomers interact with PrPC, with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ1–42 oligomers are responsible for cognitive impairment in AD and that PrPC is not required.


Trends in Neurosciences | 2012

Prion protein at the crossroads of physiology and disease.

Emiliano Biasini; Jessie A. Turnbaugh; Ursula Unterberger; David A. Harris

The presence of the cellular prion protein (PrP(C)) on the cell surface is critical for the neurotoxicity of prions. Although several biological activities have been attributed to PrP(C), a definitive demonstration of its physiological function remains elusive. In this review, we discuss some of the proposed functions of PrP(C), focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane and neuroprotection. We also discuss recent evidence supporting the idea that PrP(C) may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrP(C) and its role in neurodegenerative diseases beyond those caused by prions.


Journal of Biological Chemistry | 2013

An N-terminal Fragment of the Prion Protein Binds to Amyloid-β Oligomers and Inhibits Their Neurotoxicity in Vivo

Brian R. Fluharty; Emiliano Biasini; Matteo Stravalaci; Alessandra Sclip; Luisa Diomede; Claudia Balducci; Pietro La Vitola; Massimo Messa; Laura Colombo; Gianluigi Forloni; Tiziana Borsello; Marco Gobbi; David A. Harris

Background: The cellular prion protein (PrPC) could be a toxicity-transducing receptor for amyloid-β (Aβ) oligomers. Results: N1, a naturally occurring fragment of PrPC, binds Aβ oligomers, inhibits their polymerization into fibrils, and suppresses their neurotoxic effects in vitro and in vivo. Conclusion: N1 binds tightly to Aβ oligomers and blocks their neurotoxicity. Significance: Administration of exogenous N1 or related peptides may represent an effective therapy for Alzheimer disease. A hallmark of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide in the brain. Considerable evidence suggests that soluble Aβ oligomers are responsible for the synaptic dysfunction and cognitive deficit observed in AD. However, the mechanism by which these oligomers exert their neurotoxic effect remains unknown. Recently, it was reported that Aβ oligomers bind to the cellular prion protein with high affinity. Here, we show that N1, the main physiological cleavage fragment of the cellular prion protein, is necessary and sufficient for binding early oligomeric intermediates during Aβ polymerization into amyloid fibrils. The ability of N1 to bind Aβ oligomers is influenced by positively charged residues in two sites (positions 23–31 and 95–105) and is dependent on the length of the sequence between them. Importantly, we also show that N1 strongly suppresses Aβ oligomer toxicity in cultured murine hippocampal neurons, in a Caenorhabditis elegans-based assay, and in vivo in a mouse model of Aβ-induced memory dysfunction. These data suggest that N1, or small peptides derived from it, could be potent inhibitors of Aβ oligomer toxicity and represent an entirely new class of therapeutic agents for AD.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

Shaoman Yin; Nancy Pham; Shuiliang Yu; Chaoyang Li; Poki Wong; Binggong Chang; Shin Chung Kang; Emiliano Biasini; Po Tien; David A. Harris; Man Sun Sy

Mutation in the prion gene PRNP accounts for 10–15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrPC). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brain-derived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrPC. Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.


Journal of Neurochemistry | 2003

Proteasome inhibition and aggregation in Parkinson's disease: a comparative study in untransfected and transfected cells

Emiliano Biasini; Luana Fioriti; Ilaria Ceglia; Roberto W. Invernizzi; Alessandro Bertoli; Roberto Chiesa; Gianluigi Forloni

Dysfunction of the ubiquitin‐proteasome system (UPS) has been implicated in Parkinsons disease (PD) and other neurodegenerative disorders. We have investigated the effect of UPS inhibition on the metabolism of α‐synuclein (SYN) and parkin, two proteins genetically and histopathologically associated to PD. Pharmacological inhibition of proteasome induced accumulation of both parkin and SYN in transfected PC12 cells. We found that this effect was caused by increased protein synthesis rather than impairment of protein degradation, suggesting that inhibition of the UPS might lead to non‐specific up‐regulation of cytomegalovirus (CMV)‐driven transcription. To investigate whether endogenous parkin and SYN can be substrate of the UPS, untransfected PC12 cells and primary mesencephalic neurones were exposed to proteasome inhibitors, and parkin and SYN expression was evaluated at both protein and mRNA level. Under these conditions, we found that proteasome inhibitors did not affect the level of endogenous parkin and SYN. However, we confirmed that dopaminergic neurones were selectively vulnerable to the toxicity of proteasome inhibitors. Our results indicate that studies involving the use of proteasome inhibitors, particularly those in which proteins are expressed from a heterologous promoter, are subjected to potential artefacts that need to be considered for the interpretation of the role of UPS in PD pathogenesis.


The Journal of Neuroscience | 2008

Aggregated, Wild-Type Prion Protein Causes Neurological Dysfunction and Synaptic Abnormalities

Roberto Chiesa; Pedro Piccardo; Emiliano Biasini; Bernardino Ghetti; David A. Harris

The neurotoxic forms of the prion protein (PrP) that cause neurodegeneration in prion diseases remain to be conclusively identified. Considerable evidence points to the importance of noninfectious oligomers of PrP in the pathogenic process. In this study, we describe lines of Tg(WT) transgenic mice that over-express wild-type PrP by either ∼5-fold or ∼10-fold (depending on whether the transgene array is, respectively, hemizygous or homozygous). Homozygous but not hemizygous Tg(WT) mice develop a spontaneous neurodegenerative illness characterized clinically by tremor and paresis. Both kinds of mice accumulate large numbers of punctate PrP deposits in the molecular layer of the cerebellum as well as in several other brain regions, and they display abnormally enlarged synaptic terminals accompanied by a dramatic proliferation of membranous structures. The over-expressed PrP in Tg(WT) mice assembles into an insoluble form that is mildly protease-resistant and is recognizable by aggregation-specific antibodies, but that is not infectious in transmission experiments. Together, our results demonstrate that noninfectious aggregates of wild-type PrP are neurotoxic, particularly to synapses, and they suggest common pathogenic mechanisms shared by prion diseases and nontransmissible neurodegenerative disorders associated with protein misfolding.


The Journal of Neuroscience | 2012

The N-Terminal, Polybasic Region of PrPC Dictates the Efficiency of Prion Propagation by Binding to PrPSc

Jessie A. Turnbaugh; Ursula Unterberger; Paula Saá; Tania Massignan; Brian R. Fluharty; Frederick P. Bowman; Michael B. Miller; Surachai Supattapone; Emiliano Biasini; David A. Harris

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrPSc) binds to the cellular form (PrPC), generating additional molecules of PrPSc. While several regions of the PrPC molecule have been suggested to play a role in PrPSc formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23–31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrPSc. These results, in combination with biochemical data, demonstrate that residues 23–31 represent a critical site on PrPC that binds to PrPSc and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrPC.


Journal of Neurochemistry | 2008

Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies.

Emiliano Biasini; M. Esa Seegulam; Brianna N. Patti; Laura Solforosi; Andrea Z. Medrano; Heather M. Christensen; Assunta Senatore; Roberto Chiesa; R. Anthony Williamson; David A. Harris

The key event in the pathogenesis of prion diseases is the conformational conversion of the normal prion protein (PrP) (PrPC) into an infectious, aggregated isoform (PrPSc) that has a high content of β‐sheet. Historically, a great deal of effort has been devoted to developing antibodies that specifically recognize PrPSc but not PrPC, as such antibodies would have enormous diagnostic and experimental value. A mouse monoclonal IgM antibody (designated 15B3) and three PrP motif‐grafted monoclonal antibodies (referred to as IgG 19–33, 89–112, and 136–158) have been previously reported to react specifically with infectious PrPSc but not PrPC. In this study, we extend the characterization of these four antibodies by testing their ability to immunoprecipitate and immunostain infectious and non‐infectious aggregates of wild‐type, mutant, and recombinant PrP. We find that 15B3 as well as the motif‐grafted antibodies recognize multiple types of aggregated PrP, both infectious and non‐infectious, including forms found in brain, in transfected cells, and induced in vitro from purified recombinant protein. These antibodies are exquisitely selective for aggregated PrP, and do not react with soluble PrP even when present in vast excess. Our results suggest that 15B3 and the motif‐grafted antibodies recognize structural features common to both infectious and non‐infectious aggregates of PrP. Our study extends the utility of these antibodies for diagnostic and experimental purposes, and it provides new insight into the structural changes that accompany PrP oligomerization and prion propagation.


Journal of Biological Chemistry | 2011

An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity

Isaac H. Solomon; Natasha Khatri; Emiliano Biasini; Tania Massignan; James E. Huettner; David A. Harris

There is evidence that alterations in the normal physiological activity of PrPC contribute to prion-induced neurotoxicity. This mechanism has been difficult to investigate, however, because the normal function of PrPC has remained obscure, and there are no assays available to measure it. We recently reported that cells expressing PrP deleted for residues 105–125 exhibit spontaneous ionic currents and hypersensitivity to certain classes of cationic drugs. Here, we utilize cell culture assays based on these two phenomena to test how changes in PrP sequence and/or cellular localization affect the functional activity of the protein. We report that the toxic activity of Δ105–125 PrP requires localization to the plasma membrane and depends on the presence of a polybasic amino acid segment at the N terminus of PrP. Several different deletions spanning the central region as well as three disease-associated point mutations also confer toxic activity on PrP. The sequence domains identified in our study are also critical for PrPSc formation, suggesting that common structural features may govern both the functional activity of PrPC and its conversion to PrPSc.


Journal of Biological Chemistry | 2010

A Novel, Drug-based, Cellular Assay for the Activity of Neurotoxic Mutants of the Prion Protein *□

Tania Massignan; Richard S. Stewart; Emiliano Biasini; Isaac H. Solomon; Valentina Bonetto; Roberto Chiesa; David A. Harris

In prion diseases, the infectious isoform of the prion protein (PrPSc) may subvert a normal, physiological activity of the cellular isoform (PrPC). A deletion mutant of the prion protein (Δ105–125) that produces a neonatal lethal phenotype when expressed in transgenic mice provides a window into the normal function of PrPC and how it can be corrupted to produce neurotoxic effects. We report here the surprising and unexpected observation that cells expressing Δ105–125 PrP and related mutants are hypersensitive to the toxic effects of two classes of antibiotics (aminoglycosides and bleomycin analogues) that are commonly used for selection of stably transfected cell lines. This unusual phenomenon mimics several essential features of Δ105–125 PrP toxicity seen in transgenic mice, including rescue by co-expression of wild type PrP. Cells expressing Δ105–125 PrP are susceptible to drug toxicity within minutes, suggesting that the mutant protein enhances cellular accumulation of these cationic compounds. Our results establish a screenable cellular phenotype for the activity of neurotoxic forms of PrP, and they suggest possible mechanisms by which these molecules could produce their pathological effects in vivo.

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Tania Massignan

Mario Negri Institute for Pharmacological Research

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Roberto Chiesa

Mario Negri Institute for Pharmacological Research

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Matteo Stravalaci

Mario Negri Institute for Pharmacological Research

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Marco Gobbi

University of Strasbourg

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Gianluigi Forloni

Mario Negri Institute for Pharmacological Research

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Mario Salmona

Mario Negri Institute for Pharmacological Research

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Isaac H. Solomon

Brigham and Women's Hospital

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