Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease

Lansbury, Peter T.

doi:10.1073/pnas.96.7.3342

Cited by 540 publications

(382 citation statements)

References 37 publications

(51 reference statements)

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“…However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al, 1983;Pan et al, 1993;Safar et al, 1993;Baldwin et al, 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al, 1993;Safar et al, 1993;Baldwin et al, 1994).Structural changes similar to the PrP C to PrP SC conformational conversion associated with prion diseases are typical in amyloidoses such as Alzheimer's disease, primary systemic amyloidosis, familial amyloid polyneuropathy, and type II diabetes (Gabizon and Prusiner, 1990;Sipe, 1992;Kelly, 1996;Taubes, 1996;Lansbury, 1999). Both the amyloidoses and the prion diseases are thought to result from the conversion of normally soluble and functional proteins into abnormal ␤-sheet-rich structures that have propensities to fibrilize (Colon and…”

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confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

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Prion diseases are neurodegenerative disorders associated with a conformational change in the normal cellular isoform of the prion protein, PrP C , to an abnormal scrapie isoform, PrP SC . Unlike the ␣-helical PrP C , the protease-resistant core of PrP SC is predominantly ␤-sheet and possesses a tendency to polymerize into amyloid fibrils. We performed experiments with two synthetic human prion peptides, and , to determine how peptide structure affects neurotoxicity and protein-membrane interactions. Peptide solutions possessing ␤-sheet and amyloid structures were neurotoxic to PC12 cells in vitro and bound with measurable affinities to cholesterol-rich phospholipid membranes at ambient conditions, but peptide solutions lacking stable ␤-sheet structures and amyloid content were nontoxic and possessed less than one tenth of the binding affinities of the amyloid-containing peptides. Regardless of structure, the peptide binding affinities to cholesterol-depleted membranes were greatly reduced. These results suggest that the ␤-sheet and amyloid structures of the prion peptides give rise to their toxicity and membrane binding affinities and that membrane binding affinity, especially in cholesterol-rich environments, may be related to toxicity. Our results may have significance in understanding the role of the fibrillogenic cerebral deposits associated with some of the prion diseases in neurodegeneration and may have implications for other amyloidoses. Key Words: Circular dichroismSpongiform encephalopathies-Cell membranes. J. Neurochem. 75, 2536Neurochem. 75, -2545Neurochem. 75, (2000.The prion-related encephalopathies, including scrapie and bovine spongiform encephalopathy in livestock and Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru in humans, are neurodegenerative disorders characterized by early synaptic loss, astrocytosis, progressive neuronal loss, and often cerebral protein aggregation and deposition (Gajdusek et al., 1966;Clinton et al., 1993;Fraser, 1993;Jeffrey et al., 1994). These diseases appear to be caused by the posttranslational and conformational transition of the normal cellular prion protein (PrP) isoform, PrP C , into the abnormal and pathogenic PrP isoform, PrP SC (Prusiner, 1982(Prusiner, , 1991Hope and Manson, 1991). Fourier transform infrared spectroscopy and circular dichroism (CD) demonstrate that PrP C is predominantly ␣-helical (42%) with little ␤-sheet structure (3%). However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al., 1983;Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994).Structural changes similar to the PrP C to PrP SC conformational conversion associated with prion diseases ar...

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confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

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“…Their clinical relevance has been shown for instance in cataract formation (1) and in familial encephalopathy with neuroserpin inclusions (2); also, it is highly likely in early onset Parkinson's disease (3). In addition, there are some recurring correlations between fibrillar pathologies and disease-associated mutations, as in some familial systemic amyloidoses, Huntington's disease, and early onset Parkinson's disease (4). These correlations strongly suggest that fibril formation initiates the pathological events and that it is not an unavoidable epiphenomenon.…”

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confidence: 99%

Lithostathine Quadruple-helical Filaments Form Proteinase K-resistant Deposits in Creutzfeldt-Jakob Disease

Laurine

Grégoire

Fändrich³

et al. 2003

Journal of Biological Chemistry

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Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Strä ussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6 ]bibenzothiazolyl-2,2 -diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

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“…At least 18 different amyloidogenic proteins have been identified, and among human disorders associated with their deposition are Alzheimer's disease, Parkinson's disease, adult (type 2) diabetes, chronic inflammation, and monoclonal plasma cell dyscrasias (1)(2)(3)(4). The continual accumulation of fibrils within tissues leads to organ dysfunction and, with rare exception, is an irreversible process leading to death (5,6).…”

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confidence: 99%

“…The amyloidoses represent a group of diseases characterized by the pathological deposition of insoluble fibrils, having a characteristic non-native intermolecular ␤-sheet structure, which are formed from proteins that originally have soluble, native conformations (1)(2)(3). At least 18 different amyloidogenic proteins have been identified, and among human disorders associated with their deposition are Alzheimer's disease, Parkinson's disease, adult (type 2) diabetes, chronic inflammation, and monoclonal plasma cell dyscrasias (1)(2)(3)(4).…”

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confidence: 99%

Thermodynamic Modulation of Light Chain Amyloid Fibril Formation

Kim¹,

Wall²,

Meyer³

et al. 2000

Journal of Biological Chemistry

133

131

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To obtain further insight into the pathogenesis of amyloidosis and develop therapeutic strategies to inhibit fibril formation we investigated: 1) the relationship between intrinsic physical properties (thermodynamic stability and hydrogen-deuterium (H-D) exchange rates) and the propensity of human immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects of extrinsically modulating these properties on fibril formation. An amyloid-associated protein readily formed amyloid fibrils in vitro and had a lower free energy of unfolding than a homologous nonpathological protein, which did not form fibrils in vitro. H-D exchange was much faster for the pathological protein, suggesting it had a greater fraction of partially folded molecules. The thermodynamic stabilizer sucrose completely inhibited fibril formation by the pathological protein and shifted the values for its physical parameters to those measured for the nonpathological protein in buffer alone. Conversely, urea sufficiently destabilized the nonpathological protein such that its measured physical properties were equivalent to those of the pathological protein in buffer, and it formed fibrils. Thus, fibril formation by light chains is predominantly controlled by thermodynamic stability; and a rational strategy to inhibit amyloidosis is to design high affinity ligands that specifically increase the stability of the native protein.

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Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease

Cited by 540 publications

References 37 publications

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Lithostathine Quadruple-helical Filaments Form Proteinase K-resistant Deposits in Creutzfeldt-Jakob Disease

Thermodynamic Modulation of Light Chain Amyloid Fibril Formation

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