Mechanisms of Transthyretin Aggregation and Toxicity
Amyloidoses are characterised by the deposition of insoluble protein that occurs in the extracellular compartment of various tissues. One form of amyloidosis is caused by transthyretin (TTR) misfolding and deposition in target tissues. It is clear that ma
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Mechanisms of Transthyretin Aggregation and Toxicity Robert J. Gasperini, David W. Klaver, Xu Hou, Marie-Isabel Aguilar and David H. Small Abstract Amyloidoses are characterised by the deposition of insoluble protein that occurs in the extracellular compartment of various tissues. One form of amyloidosis is caused by transthyretin (TTR) misfolding and deposition in target tissues. It is clear that many amyloidoses share common features of fibrillogenesis and toxicity. This chapter examines the mechanisms of TTR aggregation with a view to understanding the possible therapeutic interventions in amyloid disease. Keywords Amyloid · Familial amyloidotic polyneuropathy · Fibrillogenesis · Amyloidosis · Calcium · Glycosoaminoglycans Abbreviations TTR AFM
Transthyretin Atomic force microscopy
R. J. Gasperini () Menzies Research Institute, University of Tasmania, Liverpool Street, Hobart, TAS 7001, Australia e-mail: [email protected] D. W. Klaver Department of Neuroscience, School of Medicine, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA e-mail: [email protected] X. Hou Howard Florey Institute, Parkville, VIC 3010, Australia e-mail: [email protected] M.-I. Aguilar Department of Biochemistry & Molecular Biology, Monash University, Clayton, VIC 3800, Australia e-mail: [email protected] D. H. Small Menzies Research Institute, University of Tasmania, Liverpool Street, Hobart, TAS 7001, Australia e-mail: [email protected]
J. R. Harris (ed.), Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease, Subcellular Biochemistry 65, DOI 10.1007/978-94-007-5416-4_9, © Springer Science+Business Media Dordrecht 2012
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DLS FAP Aβ Å nm kDa SSA IAPP PrP HSPG CSPG GAG VGCC TRPM8
9.1
Dynamic light scattering Familial amyloidotic polyneuropathy Amyloid beta protein Angstrom Nanometer Kilodalton Senile systemic amyloidosis Diabetes-associated islet amyloid polypeptide Prion protein Heparan sulphate proteoglycan Chondroitin sulphate proteoglycan Glycosoaminoglycan Voltage-gated calcium channel Transient receptor potential (melastatin) channel
Introduction
The amyloidoses constitute a disparate group of diseases characterised by the aggregation and extracellular deposition of insoluble protein (amyloid) in a variety of tissues. Accumulation of amyloid can lead to dysfunction of the affected organs. The underlying pathophysiology of the amyloidoses is still not completely understood and a large body of evidence now exists implicating amyloid formation in the pathogenesis of diseases such as Alzheimer’s disease, prion diseases and the British and Danish dementias. There is increasing evidence that the mechanisms of pathogenesis of amyloidoses are similar and that it is the conformation of the amyloid, rather than the specific amino-acid sequence that is the key determinant of disease progression and toxicity (Bucciantini et al. 2002). A striking, but common feature of all amyloids is their high β-sheet content and their fibrillar ult
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