A kinetic model for amyloid formation in the prion diseases: importance of seeding.

Come, Jon H.; Fraser, Paul E.; Lansbury, Peter T.

doi:10.1073/pnas.90.13.5959

Cited by 373 publications

(287 citation statements)

References 38 publications

(51 reference statements)

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“…Our observations suggest that self-assembling of Ab(1-40) from oligomers to fibrils involves the central (aa [17][18][19][20][21][22][23][24] and C-terminal parts (aa 30-40) of the peptide (Fig. 3).…”

Section: Discussionmentioning

confidence: 71%

“…Fibrils formation has been shown to occur by a nucleation-dependent kinetics, whereas the ratedetermining key step is the formation of oligomers, after which fibrillization rapidly takes place [22]. Subsequent experiments have proved that aggregation of Ab and its self-assembly into mature fibrils do not necessarily occur in a linear way [23].…”

Section: Introductionmentioning

confidence: 99%

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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

133

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

133

119

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“…According to current models, the conformation of the prion protein fluctuates between a dominant native state, PrP C , and a series of minor conformers that self-associate in an ordered manner to produce a stable supramolecular structure, PrP Sc , composed of misfolded PrP monomers (2, 9, 10). Once a stable "seed" structure is formed, additional PrP molecules can then be recruited, leading to an autocatalytic, fast formation of PrP Sc (2,10,11). * This work was partially supported by grants from the Howard Hughes Medical Institute (to S. T. F.) and Conselho Nacional de Desenvolvimento Científico e Tecnoló gico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (to S. T. F. and F. G. F.).…”

mentioning

confidence: 99%

Formation of Soluble Oligomers and Amyloid Fibrils with Physical Properties of the Scrapie Isoform of the Prion Protein from the C-terminal Domain of Recombinant Murine Prion Protein mPrP-(121–231)

Martins

Frosoni

Martínez

et al. 2006

Journal of Biological Chemistry

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Prion diseases are fatal neurodegenerative disorders associated with conformational conversion of the cellular prion protein, PrP C , into a misfolded, protease-resistant form, PrP Sc . Here we show, for the first time, the oligomerization and fibrillization of the C-terminal domain of murine PrP, mPrP-(121-231), which lacks the entire unstructured N-terminal domain of the protein. In particular, the construct we used lacks amino acid residues 106 -120 from the so-called amyloidogenic core of PrP (residues 106 -126). Amyloid formation was accompanied by acquisition of resistance to proteinase K digestion. Aggregation of mPrP-(121-231) was investigated using a combination of biophysical and biochemical techniques at pH 4.0, 5.5, and 7.0 and at 37 and 65°C. Under partially denaturing conditions (65°C), aggregates of different morphologies ranging from soluble oligomers to mature amyloid fibrils of mPrP-(121-231) were formed. Transmission electron microscopy analysis showed that roughly spherical aggregates were readily formed when the protein was incubated at pH 5.5 and 65°C for 1 h, whereas prolonged incubation led to the formation of mature amyloid fibrils. Samples incubated at 65°C at pH 4.0 or 7.0 presented an initial mixture of oligomers and protofibrils or fibrils. Electrophoretic analysis of samples incubated at 65°C revealed formation of sodium dodecyl sulfate-resistant oligomers (dimers, trimers, and tetramers) and higher molecular weight aggregates of mPrP-(121-231). These results demonstrate that formation of an amyloid form with physical properties of PrP Sc can be achieved in the absence of the flexible N-terminal domain and, in particular, of residues 106 -120 of PrP and does not require other cellular factors or a PrP Sc template.The conformational conversion of the normal cellular isoform of the prion protein, PrP C , 4 into an abnormal pathological isoform, PrP Sc , underlies a group of fatal neurodegenerative disorders known as transmissible spongiform encephalopathies or prion diseases, which includes Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, and bovine spongiform encephalopathy in cattle (1). Neuropathologically, prion diseases are characterized by neuronal loss and astrogliosis and often by spongiform degeneration of the brain and deposition of amyloid plaques (1). The unique feature of these diseases is that, in addition to sporadic and inherited forms, they may be acquired by transmission of an infectious agent. The "proteinonly" hypothesis of prion propagation postulates that the abnormal isoform, PrP Sc , acts as a transmissible agent of the disease and self-propagates its pathological conformation using PrP C as a substrate (1).PrP Sc is defined as an aggregated form of PrP that is largely resistant to proteinase K (PK) digestion under conditions in which PrP C and most other proteins are readily degraded (2). In addition to their different stabilities to proteolytic degradation, the secondary, tertiary, and quaternary structures of PrP C and PrP Sc also differ (3-7...

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“…These newly refolded prions can further convert more proteins, leading to an exponential growth. In this way, misfolded α-synuclein may act as a template for the conversion of the native α-helix form to a pathogenic β-sheet structure (217), a reaction that may occur spontaneously or due to inherited amino acid exchanges in the prion protein (218,219). In vitro, several studies have shown that aggregation of α-synuclein occurs by a mechanism resembling prions.…”

Section: Pd As a Prion Diseasementioning

confidence: 99%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

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A kinetic model for amyloid formation in the prion diseases: importance of seeding.

Cited by 373 publications

References 38 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Formation of Soluble Oligomers and Amyloid Fibrils with Physical Properties of the Scrapie Isoform of the Prion Protein from the C-terminal Domain of Recombinant Murine Prion Protein mPrP-(121–231)

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

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