Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.
Such amyloids have been associated with (but not necessarily as the cause of) more than 50 human diseases, including amyloidosis, and may play a role in some neurodegenerative diseases. Some of these diseases are mainly sporadic and only a few cases are familial. Others are only familial. Some result from medical treatment. Prions are an infectious form of amyloids that can act as a template to convert other non-infectious forms. Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.
Amyloids have been known to arise from many different proteins. These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.
An unusual secondary structure named α sheet has been proposed as the toxic constituent of amyloid precursor proteins, but this idea is not widely accepted at present.
Definition The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch ( in Latin, from ), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumin-like proteinaceous material. The classical, histopathological definition of amyloid is an extracellular, proteinaceous fibrillar deposit exhibiting β-sheet secondary structure and identified by apple-green birefringence when stained with congo red under polarized light. These deposits often recruit various sugars and other components such as serum amyloid P component, resulting in complex, and sometimes inhomogeneous structures. Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations. A more recent, biophysical definition is broader, including any polypeptide that polymerizes to form a cross-β structure, in vivo or in vitro, inside or outside cells. Microbiologists, biochemists, biophysicists, chemists and physicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.
Biological functions Many examples of non-pathological amyloid with a well-defined physiological role have been identified in various organisms, including human. These may be termed as functional or physiological or native amyloid. Functional amyloid in Homo sapiens: Intralumenal domain of melanocyte protein PMEL Peptide/protein hormones stored as amyloids within endocrine secretory granules in the pituitary gland Receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3) Fragments of prostatic acid phosphatase and semenogelins Functional amyloid in other organisms: Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla. This suggest that many more bacteria may express curli fibrils. GvpA, forming the walls of particular Gas vesicles, i.e. the buoyancy organelles of aquatic archaea and eubacteria Fap fibrils in various species of Pseudomonas Chaplins from Streptomyces coelicolor Spidroin from Trichonephila edulis (spider) (Spider silk) Hydrophobins from Neurospora crassa and other fungi Fungal cell adhesion proteins forming cell surface amyloid regions with greatly increased binding strength Environmental biofilms according to staining with amyloid specific dyes and antibodies. Tubular sheaths encasing Methanosaeta thermophila filaments Functional amyloid acting as prions Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] or [RNQ+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p) Prion HET-s from Podospora anserina Neuron-specific isoform of CPEB from Aplysia californica (marine snail)
Amyloid toxicity The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves.
Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes. Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signalling pathway leading to apoptosis. There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntington's disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.
All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree. A wide variety of biochemical, physiological and cytological perturbations has been identified following the exposure of cells and animals to such species, independently of their identity. The oligomers have also been reported to interact with a variety of molecular targets. Hence, it is unlikely that there is a unique mechanism of toxicity or a unique cascade of cellular events. The misfolded nature of protein aggregates causes a multitude of aberrant interactions with a multitude of cellular components, including membranes, protein receptors, soluble proteins, RNAs, small metabolites, etc.
Proteins forming amyloids in human diseases To date, 37 human proteins have been found to form amyloid in pathology and be associated with well-defined diseases. The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by TTR). A table is included below.
Protein Diseases Official abbreviationβ amyloid peptide (Aβ) from Amyloid precursor proteinAlzheimer's disease, Hereditary cerebral haemorrhage with amyloidosis Aβα-synucleinParkinson's disease, Parkinson's disease dementia, Dementia with Lewy bodies, Multiple system atrophyAαSynPrPScTransmissible spongiform encephalopathy (e.g. Fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, Creutzfeldt–Jakob disease, New variant Creutzfeldt–Jakob disease)APrPMicrotubule-associated protein tauVarious forms of tauopathies (e.g. Pick's disease, Progressive supranuclear palsy, Corticobasal degeneration, Frontotemporal dementia with parkinsonism linked to chromosome 17, Argyrophilic grain disease)ATauHuntingtin exon 1Huntington's diseaseHTTex1ABri peptideFamilial British dementiaABriADan peptideFamilial Danish dementiaADanFragments of immunoglobulin light chainsLight chain amyloidosisAL Fragments of immunoglobulin heavy chainsHeavy chain amyloidosisAHfull length of N-terminal fragments of Serum amyloid A proteinAA amyloidosisAATransthyretinSenile systemic amyloidosis, Familial amyloid polyneuropathy, Familial amyloid cardiomyopathy, Leptomeningeal amyloidosisATTRβ-2 microglobulinDialysis related amyloidosis, Hereditary visceral amyloidosis (familial)Aβ2MN-terminal fragments of Apolipoprotein AIApoAI amyloidosisAApoAIC-terminally extended Apolipoprotein AII ApoAII amyloidosisAApoAIIN-terminal fragments of Apolipoprotein AIV ApoAIV amyloidosisAApoAIVApolipoprotein C-II ApoCII amyloidosisAApoCIIApolipoprotein C-III ApoCIII amyloidosisAApoCIIIfragments of GelsolinFamilial amyloidosis, Finnish typeAGelLysozymeHereditary non-neuropathic systemic amyloidosisALysfragments of Fibrinogen α chainFibrinogen amyloidosisAFibN-terminally truncated Cystatin CHereditary cerebral hemorrhage with amyloidosis, Icelandic typeACysIAPP (Amylin)Diabetes mellitus type 2, Insulinoma AIAPPCalcitoninMedullary carcinoma of the thyroid ACalAtrial natriuretic factorCardiac arrhythmias, Isolated atrial amyloidosisAANFProlactinPituitary prolactinomaAProInsulinInjection-localized amyloidosisAInsLactadherin / MedinAortic medial amyloidosisAMedLactotransferrin / LactoferrinGelatinous drop-like corneal dystrophyALacOdontogenic ameloblast-associated proteinCalcifying epithelial odontogenic tumorsAOAAPPulmonary surfactant-associated protein C (SP-C)Pulmonary alveolar proteinosisASPCLeukocyte cell-derived chemotaxin-2 (LECT-2)Renal LECT2 amyloidosisALECT2Galectin-7Lichen amyloidosis, Macular amyloidosisAGal7CorneodesmosinHypotrichosis simplex of the scalpACorC-terminal fragments of TGFBI/KeratoepithelinLattice corneal dystrophy type I, Lattice corneal dystrophy type 3A, Lattice corneal dystrophy Avellino typeAKerSemenogelin-1 (SGI)Seminal vesicle amyloidosisASem1Proteins S100A8/A9Prostate cancernoneEnfuvirtideInjection-localized amyloidosisAEnf
Molecular biology Structure
Amyloids are formed of long unbranched fibers that are characterized by an extended β-sheet secondary structure in which individual β strands (β-strands) (coloured arrows in the adjacent figure) are arranged in an orientation perpendicular to the long axis of the fiber. Such a structure is known as cross-β structure. Each individual fiber may be 7–13 nanometres in width and a few micrometres in length. The main hallmarks recognised by different disciplines to classify protein aggregates as amyloid is the presence of a fibrillar morphology with the expected diameter, detected using transmission electron microscopy (TEM) or atomic force microscopy (AFM), the presence of a cross-β secondary structure, determined with circular dichroism, FTIR, solid-state nuclear magnetic resonance (ssNMR), X-ray crystallography, or X-ray fiber diffraction (often considered the "gold-standard" test to see whether a structure contains cross-β fibres), and an ability to stain with specific dyes, such as Congo red, thioflavin T or thioflavin S.