Are β-sheet breaker peptides dissolving the therapeutic problem of Alzheimer’s disease?

Permanne, Bruno; Adessi, Céline; Fraga, Santiago; Frossard, Marie José; Saborı́o, Gabriela P.; Soto, Claudio

doi:10.1007/978-3-7091-6139-5_27

Cited by 36 publications

(23 citation statements)

References 37 publications

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“…[42][43][44] These peptides are typically designed to represent an amyloidogenic region of the sequence of the target protein with the inclusion of several proline residues, which are disfavoured in β-sheet structures and decrease the aggregation propensity of the peptides. In the current investigation, however, the A-chain and B-chain peptide sequences have not been altered and can indeed themselves assemble into fibrils.…”

Section: Discussionmentioning

confidence: 99%

The Component Polypeptide Chains of Bovine Insulin Nucleate or Inhibit Aggregation of the Parent Protein in a Conformation-dependent Manner

Devlin

Knowles

Squires

et al. 2006

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 99%

The Component Polypeptide Chains of Bovine Insulin Nucleate or Inhibit Aggregation of the Parent Protein in a Conformation-dependent Manner

Devlin

Knowles

Squires

et al. 2006

Journal of Molecular Biology

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“…Elucidation of these active species and their mode of action opens new doors for developing therapeutic approaches to ameliorate misfolding and aggregation disorders. Short peptides have been shown to be an attractive therapeutic strategy for the treatment in misfolding diseases (39). The method we have developed has the potential to be used to screen for compounds that modulate the aggregate core and redirect the aggregation process to the formation of alternative, nonamyloidogenic species.…”

Section: Discussionmentioning

confidence: 99%

Orthogonal Cross-Seeding: An Approach To Explore Protein Aggregates In Living Cells

2008

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Protein aggregation is associated with the pathology of many diseases, especially neurodegenerative diseases. A variety of structurally polymorphic aggregates or preaggregates including amyloid fibrils is accessible to any aggregating protein. Preaggregates are now believed to be the toxic culprits in pathologies rather than mature aggregates. Although clearly valuable, understanding the mechanism of formation and the structural characteristics of these prefibrillar species is currently lacking. We report here a simple new approach to map the nature of the aggregate core of transient aggregated species directly in the cell. The method is conceptually based on the highly discriminating ability of aggregates to recruit new monomeric species with equivalent molecular structure. Different soluble segments comprising parts of an amyloidogenic protein were transiently pulse-expressed in a tightly controlled, time-dependent manner along with the parent aggregating full-length protein, and their recruitment into the insoluble aggregate was monitored immunochemically. We used this approach to determine the nature of the aggregate core of the metastable aggregate species formed during the course of aggregation of a chimera containing a long polyglutamine repeat tract in a bacterial host. Strikingly, we found that different segments of the full-length protein dominated the aggregate core at different times during the course of aggregation. In its simplicity, the approach is also potentially amenable to screen also for compounds that can reshape the aggregate core and induce the formation of alternative nonamyloidogenic species.Accumulation of macroscopically observable, abnormal protein deposits is the cytological feature of many age-related neurodegenerative diseases, including Alzheimer's, Parkin-son's, and Huntington's diseases (1-3). Although the characteristic pathological aggregates are primarily made up of the fibrillar aggregated form of the disease-associated protein, multiple aggregate morphologies are accessible to each individual amyloidogenic protein. The heterogeneity of aggregate morphologies may arise from (1) variations in the environment and aggregate growth conditions (4-8), (2) different segments of the primary sequence that govern the formation of the aggregate core (8-13), or (3) complex pathways of formation, including † This project was supported by the SysMO (KOSMOBAC), the DFG (project IG 73/4-1, and the Heisenberg award IG 73/1-1) to Z.I., and by the National Institutes of Health (grant GM027616 and a 2006 NIH Director's Pioneer Award to L.M.G.).

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“…iAb5 also induces the disassembly of preformed fibrils in vitro and prevent neuronal death in neuroblastoma cultures [63]. The ability of iAb5 to inhibit and disassembly amyloid fibrils was also demonstrated in vivo, using three different animal models of AD, including transgenic mice that develop many of pathological hallmarks of AD [63][64][65][66].…”

Section: Peptide Inhibitors Of Protein Misfoldingmentioning

confidence: 99%

Anti‐Misfolding and Anti‐Fibrillization Therapies for Protein Misfolding Disorders

Martin

Soto

2010

Protein Misfolding Diseases

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Are β-sheet breaker peptides dissolving the therapeutic problem of Alzheimer’s disease?

Cited by 36 publications

References 37 publications

The Component Polypeptide Chains of Bovine Insulin Nucleate or Inhibit Aggregation of the Parent Protein in a Conformation-dependent Manner

The Component Polypeptide Chains of Bovine Insulin Nucleate or Inhibit Aggregation of the Parent Protein in a Conformation-dependent Manner

Orthogonal Cross-Seeding: An Approach To Explore Protein Aggregates In Living Cells

Anti‐Misfolding and Anti‐Fibrillization Therapies for Protein Misfolding Disorders

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