Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria

Adler‐Abramovich, Lihi; Vaks, Lilach; Carny, Ohad; Trudler, Dorit; Magno, Andrea; Caflisch, Amedeo; Frenkel, Dan; Gazit, Ehud

doi:10.1038/nchembio.1002

Cited by 399 publications

(653 citation statements)

References 28 publications

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“…Furthermore, diphenylalanine peptides are known to form well-ordered nanotubular assemblies with amyloid-like structural signatures. 8 Adler-Abramovich et al 9 have also demonstrated that oligomers of single amino-acid phenylalanine can form well-ordered fibrillar assemblies at the nano scale. Although the prominent role of the two Phe of Ab seems to indicate that aromatic p-stacking interactions are critical for fibril formation, this has been put recently to doubt by mutagenesis experiments.…”

Section: Introductionmentioning

confidence: 99%

Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Berhanu

Hansmann

2012

Protein Science

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Recent mutagenesis studies using the hydrophobic segment of Ab suggest that aromatic p-stacking interactions may not be critical for fibril formation. We have tested this conjecture by probing the effect of Leu, Ile, and Ala mutation of the aromatic Phe residues at positions 19 and 20, on the double-layer hexametric chains of Ab fragment Ab 16-22 using explicit solvent all-atom molecular dynamics. As these simulations rely on the accuracy of the utilized force fields, we first evaluated the dynamic and stability dependence on various force fields of small amyloid aggregates. These initial investigations led us to choose AMBER99SB-ILDN as force field in multiple long molecular dynamics simulations of 100 ns that probe the stability of the wild-type and mutants oligomers. Single-point and double-point mutants confirm that size and hydrophobicity are key for the aggregation and stability of the hydrophobic core region (Ab [16][17][18][19][20][21][22] ). This suggests as a venue for designing Ab aggregation inhibitors the substitution of residues (especially, Phe 19 and 20) in the hydrophobic region (Ab [16][17][18][19][20][21][22] ) with natural and non-natural amino acids of similar size and hydrophobicity.

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Section: Introductionmentioning

confidence: 99%

Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Berhanu

Hansmann

2012

Protein Science

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“…One recent study found that the nanofibrils formed by low complexity sequences of RNA-binding proteins can recruit and retain mRNAs to form cell-free RNA granules (16), an action similar to that of TIA-1. Another study observed the assembly of phenylalanine in high concentration to form fibrils, which exhibit neurotoxicity similar to pathologic prions (17). Recent research on small molecule activators of a proenzyme also unintendedly discovered small molecules, which aggregate to form prion-like nanofibrils that selectively activate pro-caspase 3 to induce cell death (18).…”

mentioning

confidence: 99%

Prion-like Nanofibrils of Small Molecules (PriSM) Selectively Inhibit Cancer Cells by Impeding Cytoskeleton Dynamics

Kuang

Long

Zhou

et al. 2014

Journal of Biological Chemistry

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“…Cross-amyloid interactions could be driven by hydrophobic associations, as the presence of hydrophobic amino acids is known to yield higher amyloidal propensity (93). Most amyloid proteins display an abundance of hydrophobic residues, which could facilitate hydrophobic associations between, for example, misfolded amyloid proteins and other amyloid proteins with different sequences.…”

Section: Implications Of A␤ Cross-amyloid Interactionsmentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

128

108

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria

Cited by 399 publications

References 28 publications

Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Prion-like Nanofibrils of Small Molecules (PriSM) Selectively Inhibit Cancer Cells by Impeding Cytoskeleton Dynamics

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

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Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria

Cited by 399 publications

References 28 publications

Side‐chain hydrophobicity and the stability of Aβ16–22 aggregates

Side‐chain hydrophobicity and the stability of Aβ16–22 aggregates

Prion-like Nanofibrils of Small Molecules (PriSM) Selectively Inhibit Cancer Cells by Impeding Cytoskeleton Dynamics

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

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Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates