Membrane interaction of off-pathway prion oligomers and lipid-induced on-pathway intermediates during prion conversion: A clue for neurotoxicity

Combet, Sophie; Cousin, Fabrice; Rézaei, Human; Noinville, Sylvie

doi:10.1016/j.bbamem.2018.12.001

Cited by 9 publications

(7 citation statements)

References 66 publications

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“…Fragmentation of PrP Sc aggregates increases the number of nuclei capable of recruiting further PrP Sc . In fact, these soluble oligomers produced during the PrP amyloid aggregation have emerged as the primary neurotoxic species, supporting the seeded nucleation model …”

Section: Mechanism Of Prpc‐prpsc Conversionmentioning

confidence: 58%

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Hackl

Becker

2019

Journal of Peptide Science

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Deciphering the pathophysiologic events in prion diseases is challenging, and the role of posttranslational modifications (PTMs) such as glypidation and glycosylation remains elusive due to the lack of homogeneous protein preparations. So far, experimental studies have been limited in directly analyzing the earliest events of the conformational change of cellular prion protein (PrPC) into scrapie prion protein (PrPSc) that further propagates PrPC misfolding and aggregation at the cellular membrane, the initial site of prion infection, and PrP misfolding, by a lack of suitably modified PrP variants. PTMs of PrP, especially attachment of the glycosylphosphatidylinositol (GPI) anchor, have been shown to be crucially involved in the PrPSc formation. To this end, semisynthesis offers a unique possibility to understand PrP behavior in vitro and in vivo as it provides access to defined site‐selectively modified PrP variants. This approach relies on the production and chemoselective linkage of peptide segments, amenable to chemical modifications, with recombinantly produced protein segments. In this article, advances in understanding PrP conversion using semisynthesis as a tool to obtain homogeneous posttranslationally modified PrP will be discussed.

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Section: Mechanism Of Prpc‐prpsc Conversionmentioning

confidence: 58%

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Hackl

Becker

2019

Journal of Peptide Science

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“…Moreover, type 1 was further shown by conformation stability immunoassay to segregate into two different strains termed T1 20 and T1 21 based on their proteinase K resistance profile and lesion pattern [121]. Off-pathway PrP oligomers [122] and nucleic acid-mediated LLPS [123] were characterized as well, further increasing the heterogeneity of possible PrP structures. Selective vulnerability of different neuronal populations may account for the formation of different strains within the same organism, as substantiated by the differences in lesion pattern.…”

Section: Prp: the Protein That Started It Allmentioning

confidence: 99%

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Candelise

Scaricamazza

Salvatori

et al. 2021

IJMS

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Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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“…The accuracy of the spectral decomposition analysis was determined by calculating standard errors from three different curve fittings using one spectrum over the overall spectra as a reference model. The component bands were assigned according to our previous work [24,25,36] and according to the infrared analysis of structured or -aggregated proteins [37,38].…”

Section: Semi-quantitative Analysis Of Adsorbed Protein Secondary Structurementioning

confidence: 99%

“…We can then propose from the SLS-ThT binding assays that a concentration threshold is needed to produce the lipid-induced full-length moPrPfibrillation, whereas this is not the case for moH2H3. Considering the co-existence of polydispersed species formed during the lipid-induced fibrillation, it is difficult to decipher which oligomeric species would be membrane-active in the case of the full-length protein [25,58]. Working at concentrations below 300 nM ensured that the moPrP molecules remained in the monomeric state for the duration of the BLM experiments.…”

Section: Link Between Lipid-bound Conformational States Of Monomers and Membrane Impairmentmentioning

confidence: 99%

“…One of the problems associated with these investigations is related to the fact that the oligomeric species are often unstable, making detailed structural analyses difficult [23]. In our previous works, we laid emphasis on the role of purified oligomers of the full-length and Nterminally truncated forms of PrP compared to the corresponding monomers on negatively charged vesicles [24,25]. Both oligomeric constructs possess the lipid-bound transmembrane domain PrP , but this domain is differently accessible in the -sheeted 12-mers for membrane binding depending on the monomer primary sequence.…”

Section: Introductionmentioning

confidence: 99%

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Conformation-dependent membrane permeabilization by neurotoxic PrP oligomers: The role of the H2H3 oligomerization domain

Huin

Cronier

Guégan

et al. 2020

Archives of Biochemistry and Biophysics

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The relationship between prion propagation and the generation of neurotoxic species and clinical onset remains unclear. Several converging lines of evidence suggest that interactions with lipids promote various precursors to form aggregation-prone states that are involved in amyloid fibrils. Here, we compared the cytotoxicities of different soluble isolated oligomeric constructs from murine full-length PrP and from the restricted helical H2H3 domain with their effects on lipid vesicles. The helical H2H3 domain is suggested to be the minimal region of PrP involved in the oligomerization process. The discrete PrP oligomers of both the full-length sequence and the H2H3 domain have de novo -sheeted structure when interacting with the membrane. They were shown to permeabilize synthetic negatively charged vesicles in a dose-dependent manner. Restricting the polymerization domain of the full-length PrP to the H2H3 helices strongly diminished the ability of the corresponding oligomers to associate with the lipid vesicles. Furthermore, the membrane impairment mechanism occurs differently for the fulllength PrP oligomers and the H2H3 helices, as shown by dye-release and black lipid membrane experiments. The membrane damage caused by the full-length PrP oligomers is correlated to their neuronal toxicity at submicromolar concentrations, as shown by cell culture assays. Although oligomers of synthetic H2H3 could compromise in vitro cell homeostasis, they followed a membrane-disruptive pattern that was different from the full-length oligomers, as revealed by the role of PrP C in cell viability assays.

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Membrane interaction of off-pathway prion oligomers and lipid-induced on-pathway intermediates during prion conversion: A clue for neurotoxicity

Cited by 9 publications

References 66 publications

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Conformation-dependent membrane permeabilization by neurotoxic PrP oligomers: The role of the H2H3 oligomerization domain

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