Suppression of IAPP fibrillation at anionic lipid membranes via IAPP-derived amyloid inhibitors and insulin

Sellin, Daniel; Yan, Limei; Kapurniotu, Aphrodite; Winter, Roland

doi:10.1016/j.bpc.2010.01.006

Cited by 68 publications

(74 citation statements)

References 30 publications

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“…Likewise, in transthyretin (TTR) amyloid diseases, murine/human TTR homologs form heterotetramers that impair amyloid formation (51,52), and aggregation in vivo was achieved mostly in Tg mice expressing TTR mutants on an endogenous TTR-KO background (52). Finally, the aggregation kinetics of the islet amyloid polypeptide (IAPP) in bulk solution was reduced dramatically by the presence of its rat homolog (53,54).…”

Section: Discussionmentioning

confidence: 91%

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

Fares

Maco

Oueslati

et al. 2016

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

103

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Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, hα-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous hα-Syn and endogenous mouse synuclein homologs could be attenuating hα-Syn fibrillization in mice, and therefore, we systematically assessed hα-Syn aggregation propensity in neurons derived from α-Syn-KO, β-Syn-KO, γ-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of α-Syn-KO, β-Syn-KO, and triple-KO mice, as well as in transgenic α-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investigated whether the presence of homologous α-Syn species would interfere with the seeding and spreading of α-Syn pathology. Our results are in line with increasing evidence demonstrating that the spreading of α-Syn pathology is most prominent when the injected preformed fibrils and host-expressed α-Syn monomers are from the same species. These findings provide insights that will help advance the development of neuronal and in vivo models for understanding mechanisms underlying hα-Syn intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of α-Syn fibrillization in neurons.Parkinson's disease | alpha-synuclein | aggregation T he aggregation of proteins into fibrillar structures is a key hallmark of many neurodegenerative disorders. In Parkinson's disease (PD), α-synuclein (α-Syn), a predominantly presynaptic protein involved in the regulation of neurotransmitter release, abnormally fibrilizes and forms intraneuronal inclusions termed "Lewy bodies" (LBs) (1, 2). So far, the mechanisms underlying LB formation remain poorly understood, and the impact of LB presence on neuronal viability remains controversial, in part due to the lack of animal models recapitulating α-Syn fibrillization into LB-like inclusions in the brain.Because patients with familial history of parkinsonism were found carrying either multiplications or point mutations of the α-Syn gene SNCA (2), most animal models of PD have been generated by overexpressing WT human α-Syn (hα-Syn) or mutant forms linked to familial PD (3). Strikingly, although rodent models expressing hα-Syn do not recapitulate the formation of fibrillar LBs within dopaminergic neurons, hα-Syn overexpression in Drosophila led to dramatic neuronal loss accompanied with LB-like structures compri...

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Section: Discussionmentioning

confidence: 91%

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

Fares

Maco

Oueslati

et al. 2016

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

103

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“…Nonnatural mutations, such as the inclusion of N-methylated amino acids (25) and the I26P mutant used in this work, further show that altering the FGAIL sequence dramatically affects the aggregation of hIAPP. In fact, peptide inhibitors that slow down or prevent hIAPP fibrillization often have mutations near residues 20-29 (23,41,42). Of course, mutations outside this region can play an important role by destabilizing the fibril itself (21,22) and the aggregation pathway may be different in vivo or at different concentrations (43,44).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Buchanan

Dunkelberger

Tran

et al. 2013

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

236

345

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Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.inhibitors | aggregation pathway | vibrational coupling T he misfolding of proteins into β-sheet-rich amyloid fibrils is associated with the pathology of more than 20 human diseases, including Alzheimer's, Parkinson, and Huntington diseases (1). Amyloid plaques are formed by masses of fibrils, but growing evidence suggests that the toxic species may be prefibrillar intermediates (2, 3). As a result, there is much interest in understanding the mechanism by which these proteins form fibrils and identifying intermediates in the aggregation pathway. However, obtaining structural information about intermediate species is difficult due to their transient nature. Solid-state NMR (ssNMR) and X-ray crystallography provide high-resolution structures of fibrils (4, 5) and optical techniques can track structural changes in real time (6, 7), but few techniques have both the structural and the temporal resolution to extract specific structural details about intermediates. Fragments have been trapped in intriguing oligomeric structures that may represent intermediate states (5,8) and transient secondary structures are known to exist from circular dichroism measurements and other experiments (9-11), but for full-length proteins it has been difficult to identify the specific residues that contribute to the secondary structure and thus understand their role in the aggregation mechanism. In this paper, we use 2D infrared (2D IR) spectroscopy and isotope labeling to monitor the structural evolution of the full-length human islet amyloid polypeptide (hIAPP or amylin), a 37-residue peptide implicated in type 2 diabetes. We observe the formation of a structured prefibrillar intermediate in a region that has long been known to influence aggregation, but that does not form well-ordered cross-β structure in the amyloid fibril. Its presence provides unique structural insights into the mechanism of amyloid aggregation and helps unify many seemingly inconsistent prior studies.Many studies on hIAPP have focused ...

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“…The observation in the present study implies that the binding of the all-D-amino-acid inhibitor with hIAPP oligomeric intermediates inhibits the cytotoxicity. The study of Sellin et al on the inhibition of hIAPP fibrillation at lipid membrane surface has demonstrated that the interaction of hIAPP with lipid membrane can be completely abolished in the presence of NFGAIL-GI, a peptide inhibitor from the N-methylation of the backbone amides at G and I of NFGAIL, and the sequestration of hIAPP in the aqueous phase was accounted for the observed strong inhibitory effect of NFGAIL-GI on hIAPP fibrillization [11]. The same thing may happen in our study.…”

Section: The Inhibition Effect In Cellsmentioning

confidence: 99%

“…Whereas most of the studies were performed in bulk solution [6][7][8][9], few works were done at membrane surfaces [10][11][12]. However, compared with the study in bulk solution, the study at lipid membrane interface should be more important because hIAPP-induced toxicity in diabetes involves interactions between the cell membrane and misfolded protein.…”

Section: Introductionmentioning

confidence: 99%

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Wang

Lei

et al. 2014

FEBS Letters

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Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

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Suppression of IAPP fibrillation at anionic lipid membranes via IAPP-derived amyloid inhibitors and insulin

Cited by 68 publications

References 30 publications

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

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