Role of Prion Protein Aggregation in Neurotoxicity

Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Nizzari, Mario; Florio, Tullio

doi:10.3390/ijms13078648

Cited by 40 publications

(37 citation statements)

References 130 publications

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“…The infectious agent of TSEs is a misfolded protein, referred to as PRP sc [14]. PRP sc aggregates can self-propagate and elongate by binding to monomers of PrP c (normal prion protein) [15].…”

Section: Prion-like Phenomena In Alsmentioning

confidence: 99%

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

Lee

Kim

2015

Exp Neurobiol

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ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.

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Section: Prion-like Phenomena In Alsmentioning

confidence: 99%

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

Lee

Kim

2015

Exp Neurobiol

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“…PrP C is considered at the basis of the pathogenesis of prion diseases, in which the fundamental event is its misfolding into a protease-insensitive, amyloidogenic isoform (PrP Sc ) [1]. Misfolded PrP C accumulates in intra- and extracellular deposits as insoluble protein aggregates [2, 3] responsible of neurotoxicity and astrogliosis [4–8]. The conversion of PrP C into PrP Sc consists in a radical modification of its three-dimensional structure and, consequently, of its biochemical and biological properties [9–11].…”

Section: Introductionmentioning

confidence: 99%

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

et al. 2016

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Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.

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“…According to the widely-accepted 'protein only' hypothesis, TSE pathogenesis is related to the transformation of a hostencoded, soluble and protease-sensitive prion protein (PrP C ) into an insoluble and protease-resistant, disease-associated isoform called (PrP Sc ) which could propagate itself by transferring its abnormal conformation on newly syntheized PrP C molecules which accumulate in the central nervous system causing the disease [34,35,36].…”

Section: Spiroplasmas As Suspected Causative Agents Of Transmissible mentioning

confidence: 99%

Spiroplasma – an emerging arthropod-borne pathogen?

Cisak

Wójcik-Fatla

Zając

et al. 2015

Ann Agric Environ Med.

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Spiroplasma is a genus of wall-less, low-GC, small Gram-positive bacteria of the internal contractile cytoskeleton, with helical morphology and motility. The genus is classified within the class Mollicutes. Spiroplasma / host interactions can be classified as commensal, pathogenic or mutualist. The majority of spiroplasmas are found to be commensals of insects, arachnids, crustaceans or plants, whereas a small number of species are pathogens of plants, insects, and crustaceans. Insects are particularly rich sources of spiroplasmas. The bacteria are common in haematophagous arthropods: deerflies, horseflies, mosquitoes, and in ticks, where they may occur abundantly in salivary glands. The ability of spiroplasmas to propagate in rodents was experimentally proven, and Spiroplasma infections have been reported recently in humans. Some authors have purported an etiological role of Spiroplasma in causing transmissible spongiform encephalopathies (TSEs), but convincing proof is lacking. The possibility for humans and other vertebrates to be infected with Spiroplasma spp. in natural conditions is largely unknown, as well as the possibility of the transmission of these bacteria by ticks and haematophagous insects. Nevertheless, in the light of new data, such possibilities cannot be excluded.

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Role of Prion Protein Aggregation in Neurotoxicity

Cited by 40 publications

References 130 publications

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Spiroplasma – an emerging arthropod-borne pathogen?

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