A Peptidomimetic Approach to Targeting Pre-amyloidogenic States in Type II Diabetes

Hebda, James A.; Saraogi, Ishu; Magzoub, Mazin; Hamilton, Andrew D.; Miranker, Andrew D.

doi:10.1016/j.chembiol.2009.08.013

Cited by 92 publications

(116 citation statements)

References 56 publications

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“…The question has been asked as to whether any of these α-helical and presumably early folding intermediates can represent toxic species amenable to therapeutic targeting (39). A peptidomimetic approach targeting α-helical IAPP intermediates inhibited fiber formation under lipid-catalyzed conditions and attenuated IAPPinduced toxicity (50). Herein, we provide unique experimental evidence that a highly α-helical amyloidogenic protein is strongly neurotoxic.…”

Section: Discussionmentioning

confidence: 85%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuronal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrP Sc ). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly α-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric α-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms.

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Section: Discussionmentioning

confidence: 85%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Other relevant physiological elements include the effects of binding partners, such as insulin, and increased temperature. We have previously shown that structure-based small molecules that target the non-amyloid, membrane stabilized α-helical states of IAPP are protective of IAPP-induced toxicity in cell culture (14). This suggests that the leakage properties observed here, mediated by non-amyloid membrane conformers, will serve as important surrogates in other efforts aimed at understanding the in vivo effects of insulin, temperature, protein concentration, and membrane chemistry, and their potential relevance to therapeutic development.…”

Section: Discussionmentioning

confidence: 93%

“…Furthermore, structure-based small-molecule targeting of this α-helix is protective of human IAPP toxicity in cell culture (14). Thus, rodent IAPP provides an excellent opportunity to study relevant aspects of preamyloidogenic assemblies of IAPP without the practical restrictions of losing protein to amyloid formation itself.…”

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confidence: 99%

Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity

Last

Rhoades

Miranker

2011

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid fiber formation is correlated with pathology in many diseases, including Alzheimer's, Parkinson's, and type II diabetes. Although β-sheet-rich fibrillar protein deposits define this class of disorder, increasing evidence points toward small oligomeric species as being responsible for cell dysfunction and death. The molecular mechanism by which this occurs is unknown, but likely involves the interaction of these species with biological membranes, with a subsequent loss of integrity. Here, we investigate islet amyloid polypeptide, which is implicated in the loss of insulin-secreting cells in type II diabetics. We report the discovery of oligomeric species that arise through stochastic nucleation on membranes and result in disruption of the lipid bilayer. These species are stable, result in all-or-none leakage, and represent a definable protein/lipid phase that equilibrates over time. We characterize the reaction pathway of assembly through the use of an experimental design that includes both ensemble and single-particle evaluations. Complexity in the reaction pathway could not be satisfied using a two-state description of membrane-bound monomer and oligomeric species. We therefore put forward a threestate kinetic framework, one of which we conjecture represents a non-amyloid, non-β-sheet intermediate previously shown to be a candidate therapeutic target.amylin | membrane pore | cytotoxicity | disordered protein A lzheimer's, Parkinson's, type II diabetes, and other epidemiologically important diseases are characterized, in part, by the deposition of proteinaceous plaques termed amyloid (1, 2). For each disease, a specific protein is involved in amyloid assembly via a process that is cytotoxic, ultimately leading to degeneration. Although a defining characteristic, it is now widely thought that these deposits are not the origin of cytotoxicity. Instead, it has been suggested that cell dysfunction and death are mediated by small oligomeric species that acquire the capacity to disrupt cellular membrane integrity (3, 4). The energetic and structural basis by which these states mediate toxicity, however, is unclear.Islet amyloid polypeptide (IAPP or amylin) is a 37-residue peptide hormone cosecreted with insulin by pancreatic β-cells. Unmodified, wild-type IAPP self-assembles to form amyloid in type II diabetic patients in a process that is associated with β-cell dysfunction (2, 5). Indeed, the capacity of species-based sequence variants to form amyloid is correlated with the observation of metabolic disease (6). Thus, whereas primates and cats readily form amyloid and acquire diabetes, rats and mice do not spontaneously develop diabetes, and rodent IAPP does not form amyloid or other β-sheet aggregates. Diabetic symptoms can be induced in model rodents either by using toxins or by using rodents transgenic for human IAPP (7).Previous in vitro studies have shown that the binding of human and rat IAPP to lipid bilayers is cooperative (8), an observation accounted for by the presence of oligomeric species. The pop...

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“…It would be of interest to test if α-helical monomeric species are generated en route to oligomerization from α-synuclein mutants that exhibit in vivo toxicity [11]. A peptidomimetic approach targeting α-helical IAPP intermediates inhibited fiber formation under lipid-catalyzed conditions and attenuated IAPP-induced toxicity [30]. TPrP provides "The finding of TPrP as a highly toxic species raises the possibility that misfolded protein monomers play a hitherto underestimated role.…”

mentioning

confidence: 99%