Synthetic prions and other human neurodegenerative proteinopathies

Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Trần, Hương Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

doi:10.1016/j.virusres.2014.10.020

Cited by 14 publications

(12 citation statements)

References 136 publications

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“…For instance, amyloids are associated with fungal surface-structures and the recent observation of amyloidogenic fungal proteins and diffuse mycoses in the blood of AD patients suggest that chronic fungal infection over the course of aging may increase AD risk (Alonso et al, 2014; Hill et al, 2014). Of further relevance is that: (i) Aβ42 peptide monomers, dimers, oligomers and fibrils each induce patterns of pro-inflammatory gene signaling typical of the classical microglial-mediated innate-immune and inflammatory response induced by infectious agents such as bacterial LPS (Ferrera et al, 2014; Calsolaro and Edison, 2016; Lukiw, 2016; Andreeva et al, 2017); (ii) the presence of bacterial LPS or endotoxin/exotoxin-mediated inflammatory signaling strongly contributes to amyloid neurotoxicity (Lee et al, 2008; Asti and Gioglio, 2014; Zhao and Lukiw, 2015; Zhao et al, 2016); (iii) AD amyloids, like prion amyloids, once formed, may induce a self-perpetuating process leading to amplification, aggregation, and spreading of pathological aggregates (Le et al, 2014); and (iv) recently it has been shown that Aβ42 peptide fibrillogenesis is strongly potentiated by soluble bacterial exudates and viruses such as HSV-1, suggesting the contribution of microbial-sourced factors and/or infectious events to amyloidogenesis, a distinguishing feature of the AD neuropathology (Hill et al, 2014; Stilling et al, 2014; Zhao et al, 2015; Russo et al, 2017). …”

Section: Amyloidsmentioning

confidence: 99%

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

Zhao

Jaber

Lukiw

2017

Front. Cell. Infect. Microbiol.

283

297

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Although the potential contribution of the human gastrointestinal (GI) tract microbiome to human health, aging, and disease is becoming increasingly acknowledged, the molecular mechanics and signaling pathways of just how this is accomplished is not well-understood. Major bacterial species of the GI tract, such as the abundant Gram-negative bacilli Bacteroides fragilis (B. fragilis) and Escherichia coli (E. coli), secrete a remarkably complex array of pro-inflammatory neurotoxins which, when released from the confines of the healthy GI tract, are pathogenic and highly detrimental to the homeostatic function of neurons in the central nervous system (CNS). For the first time here we report the presence of bacterial lipopolysaccharide (LPS) in brain lysates from the hippocampus and superior temporal lobe neocortex of Alzheimer's disease (AD) brains. Mean LPS levels varied from two-fold increases in the neocortex to three-fold increases in the hippocampus, AD over age-matched controls, however some samples from advanced AD hippocampal cases exhibited up to a 26-fold increase in LPS over age-matched controls. This “Perspectives” paper will further highlight some very recent research on GI tract microbiome signaling to the human CNS, and will update current findings that implicate GI tract microbiome-derived LPS as an important internal contributor to inflammatory degeneration in the CNS.

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Section: Amyloidsmentioning

confidence: 99%

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

Zhao

Jaber

Lukiw

2017

Front. Cell. Infect. Microbiol.

283

297

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“…First, we employed an amyloid-infected cell culture assay for screening amyloid preparations, in order to evaluate putative infectious materials [ 25 ]. Based on this methodology, when infected into mouse hypothalamic (GT1) and mouse neuroblastoma (N2a) host cell lines [ 26 ], amyloid fibrils from different preparations induced the conversion of endogenous PrP C to mildly PK-resistant PrP isoforms.…”

Section: Introductionmentioning

confidence: 99%

Synthetic prions with novel strain-specified properties

Moda

Aulić

et al. 2015

PLoS Pathog

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Prions are infectious proteins that possess multiple self-propagating structures. The information for strains and structural specific barriers appears to be contained exclusively in the folding of the pathological isoform, PrPSc. Many recent studies determined that de novo prion strains could be generated in vitro from the structural conversion of recombinant (rec) prion protein (PrP) into amyloidal structures. Our aim was to elucidate the conformational diversity of pathological recPrP amyloids and their biological activities, as well as to gain novel insights in characterizing molecular events involved in mammalian prion conversion and propagation. To this end we generated infectious materials that possess different conformational structures. Our methodology for the prion conversion of recPrP required only purified rec full-length mouse (Mo) PrP and common chemicals. Neither infected brain extracts nor amplified PrPSc were used. Following two different in vitro protocols recMoPrP converted to amyloid fibrils without any seeding factor. Mouse hypothalamic GT1 and neuroblastoma N2a cell lines were infected with these amyloid preparations as fast screening methodology to characterize the infectious materials. Remarkably, a large number of amyloid preparations were able to induce the conformational change of endogenous PrPC to harbor several distinctive proteinase-resistant PrP forms. One such preparation was characterized in vivo habouring a synthetic prion with novel strain specified neuropathological and biochemical properties.

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“…Many features associated with the propagation of PrP-based prions, including templated seeding and cell-to-cell transmission, have now been observed in non-PrP prions. Another important property of classical PrP prions that has recently been shown in AD and PD is the occurrence of distinct phenotypic strains with unique conformational and biochemical properties (Prusiner 2013;Le et al 2014;Stohr et al 2014;Watts et al 2014;Morales et al 2015). In this review, we provide an overview of the prion-strain phenomenon and outline recent evidence that suggests that distinct conformational strains are also present in AD and PD.…”

mentioning

confidence: 99%

Biology and Genetics of PrP Prion Strains

Ghaemmaghami

2016

Cold Spring Harb Perspect Med

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Prion diseases are a group of fatal neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrP) into a pathogenic conformation (PrP). PrP is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Evidence suggests that the structural heterogeneity of PrP is the molecular basis of strain-specific prion properties. The self-templating of PrP typically ensures that prion strains breed true upon passage. However, prion strains also have the capacity to conformationally transform to maximize their rate of replication in a given environment. Here, we provide an overview of the prion-strain phenomenon and describe the role of strain adaptation in drug resistance. We also describe recent evidence that shows the presence of distinct conformational strains in other neurodegenerative disorders.

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Synthetic prions and other human neurodegenerative proteinopathies

Cited by 14 publications

References 136 publications

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

Synthetic prions with novel strain-specified properties

Biology and Genetics of PrP Prion Strains

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