Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Oskarsson, Marie E.; Singh, K. N.; Wang, Jian; Vlodavsky, Israël; Li, Jinping; Westermark, Gunilla T.

doi:10.1074/jbc.m114.631697

Cited by 41 publications

(44 citation statements)

References 57 publications

(61 reference statements)

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“…Enzymatic removal of HSPG (Oskarsson et al 2015, Potter et al 2015 or blockade of HSPG binding sites (Hull et al 2007) reduced islet amyloid formation in hIAPP transgenic mouse or human islets in vitro; this suggests that the proteoglycans are a binding site for IAPP on the outside of the cell. If HSPGs are a primary anchoring site in the extracellular space for monomeric secreted hIAPP then hIAPP/HSPG interactions could lead to a high local concentration of hIAPP and promote aggregation (Westermark 1973).…”

Section: R132 Review D Raleigh and Othersmentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

109

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Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.

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Section: R132 Review D Raleigh and Othersmentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

109

View full text Add to dashboard Cite

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“…Using cells and transgenic rodents as disease models, other studies found hIAPP fibrils to be associated with apoptosis, β-cell loss, and T2D severity (O'Brien et al, 1995; Hiddinga and Eberhardt, 1999; Janson et al, 1996; Hull et al, 2005a, 2005b; Pilkington et al, 2016). In contrast, some studies show that the process of hIAPP fibril formation, not the amyloid fibrils themselves, is the source of toxicity (Schlamadinger and Miranker, 2014; Oskarsson et al, 2015). However, most current research studies suggest soluble pre-fibrillar oligomers are the primary type of toxic aggregate.…”

Section: Introductionmentioning

confidence: 99%

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Krotee

Rodríguez

Sawaya

et al. 2017

eLife

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hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19–29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15–25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19–29 S20G may serve as a model for the toxic spine of hIAPP.DOI: http://dx.doi.org/10.7554/eLife.19273.001

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“…The absence of cell surface GAGs did not reduce the vulnerability of CHO cells towards IAPP (De Carufel et al 2013). In contrast, isolated islets of double-transgenic mice overexpressing both heparinase and hIAPP had less amyloid deposition than the islets isolated from hIAPP transgenic mice (Oskarsson et al 2015). The relation between sulfated GAGs and amyloid-related cytotoxicity was also investigated with Aβ.…”

Section: Biological Relevance Of Gag-mediated Amyloid Assemblymentioning

confidence: 99%

“…Two of these structural models describe a monomer with a disordered N-terminal domain and two segments in β-sheet conformation, where each β-strand participates in two different parallel in-register β-sheets (Paravastu et al 2008;Petkova et al 2006). The two segments are linked by a loop and monomers are stack along the fibril axis.…”

Section: Molecular Architecture Of Amyloid Fibrilsmentioning

confidence: 99%

Modulation of amyloid assembly by glycosaminoglycans: from mechanism to biological significance

Quittot

Sebastiao

Bourgault

2017

Biochem. Cell Biol.

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Abstract:Glycosaminoglycans (GAGs) are long and unbranched polysaccharides that are abundant in the extracellular matrix and basement membrane of multicellular organisms. These linear polyanionic macromolecules are involved in many physiological functions, from cell adhesion to cellular signaling. Interestingly, amyloid fibrils extracted from patients afflicted with protein misfolding diseases are virtually always associated with GAGs. Amyloid fibrils are highly organized nanostructures that have been historically associated with pathological states, such as Alzheimer's disease and systemic amyloidoses. However, recent studies have identified functional amyloids that accomplish crucial physiological roles in almost all living organisms, from bacteria to insects and mammals. Over the last two decades, numerous reports have revealed that sulfated GAGs accelerate and/or promote the self-assembly of a large diversity of proteins, both inherently amyloidogenic and non-aggregation prone. Despite the fact that many studies have investigated the molecular mechanism(s) by which GAGs induce amyloid assembly, the mechanistic elucidation of GAG-mediated amyloidogenesis still remains the subject of active research.In this review, we expose the contribution of GAGs in amyloid assembly and we discuss the pathophysiological and functional significance of GAG-mediated fibrillization. Finally, we propose mechanistic models of the unique and potent ability of sulfated GAGs to hasten amyloid fibril formation.

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Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Cited by 41 publications

References 57 publications

The β-cell assassin: IAPP cytotoxicity

The β-cell assassin: IAPP cytotoxicity

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Modulation of amyloid assembly by glycosaminoglycans: from mechanism to biological significance

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