Self-propagating beta-sheet polypeptide structures as prebiotic informational molecular entities: the amyloid world.

The idea is advanced that under the extreme earth conditions for ~3.9 billions years ago, protein-based beta-sheet molecular structures were the first self-propagating and information-processing biomolecules that evolved. The amyloid structure of these aggregates provided an effective protection against the harsh conditions known to decompose both polyribonucleotides and natively folded polypeptides. In the prebiotic amyloid world, both the replicative and informational functions were carried out by structurally stable beta-sheet protein aggregates in a prion-like mode involving templated self-propagation and storage of information in the beta-sheet conformation. In this amyloid (protein)-first, hybrid replication-metabolism view, the synthesis of RNA, and the evolvement of an RNA-protein world, were later, but necessary events for further biomolecular evolution to occur. I further argue that in our contemporary DNA<-->RNA-->protein world, the primordial beta-conformation-based information system is preserved in the form of a cytoplasmic epigenetic memory.

The emerging concept of functional amyloid.

Although amyloid has usually been considered a pathological structure, growing evidence indicates that amyloid may also be a productive part of cell biology contributing to normal physiology. In fact, amyloid formation seems to be an intrinsic propensity of polypeptides in general and the amyloid beta-fold an evolutionary highly conserved structure. Functional amyloids have been found in a wide range of organisms, from bacteria to mammals, with functions as diverse as biofilm formation, development of aerial structures, scaffolding, regulation of melanin synthesis, epigenetic control of polyamines and information transfer. Obviously, organisms have evolved taking advantage of the canonical amyloid beta-sheet fold, a conformation that possesses both high resistance to proteolysis, self-replicative properties and capability to function as a molecular memory.

Treatment strategies for amyloid A amyloidosis.

BACKGROUND: Amyloid A (AA) amyloidosis is a serious complication of a wide range of chronic inflammatory, infectious and neoplastic diseases. A longstanding overproduction of the liver-synthesised cytokine-induced acute phase serum amyloid A (SAA) protein is a key event in the pathogenetic cascade leading to the deposition of AA amyloid in tissues and organs. OBJECTIVE: The aim of the study was to critically review treatment strategies in AA amyloidosis. METHODS: A systematic literature review was conducted based on PubMed (January 1980 - April 2008) and selected conference abstracts. RESULTS/CONCLUSIONS: The current strategy for the treatment of AA amyloidosis is firmly based on the knowledge of the underlying pathogenetic mechanism and aims at reducing the amyloid precursor (SAA) load by intensive anti-inflammatory/immunosuppressive therapy and, in selected instances, anticytokine (TNF-alpha, IL-1beta or IL-6 blockade) therapy, or, when applicable, the eradication of an existing infectious focus (surgery, antimicrobial drugs). Emerging strategies focus on the dissolution of the amyloid deposits using small molecules that either interact with the glycosaminoglycans or the fibril component of the deposits, or deplete amyloid P component.

Variant mannose-binding lectin 2 genotype is a risk factor for reactive systemic amyloidosis in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to investigate whether polymorphism of the mannose-binding lectin 2 (MBL2) gene is related to the occurrence of systemic AA amyloidosis in patients with rheumatoid arthritis (RA). METHODS: MBL2 structural gene polymorphisms at codon 52 (CGT-->TGT, Arg-->Cys; D), codon 54 (GGC-->GAC, Gly-->Asp; B) and codon 57 (GGA-->GAA, Gly--> Glu; C), and MBL2 promoter region polymorphism at position -221 (G-->C) were examined in 57 patients with RA complicated by biopsy-proven reactive amyloidosis and 51 control RA patients without amyloid. RESULTS: A strong association was found between the presence of a structural MBL2 gene variant O (B, D or C) and the occurrence of amyloidosis in RA patients: 29 of 57 (50.9%) of the RA patients with amyloid had a variant allele compared with 12 of 51 (23.5%) of the RA patients without amyloid (OR 3.37, 95% CI 1.47-7.72; P = 0.004). CONCLUSION: We conclude that variant MBL2 structural genotype constitutes a significant risk factor for reactive amyloidosis in RA and that the increased risk is probably related to MBL-mediated impairment of mononuclear phagocyte function.

Molecular mechanism based on self-replicating protein conformation for the inheritance of acquired information in humans.

Recent evidence challenges the paradigmatic view of nucleic acids as the sole mediators of hereditary information. Here I present a molecular mechanism that can explain how acquired information in humans in a DNA independent mode becomes innate and heritable. The model is based on self-replicating protein conformations, a concept derived from prion and amyloid biology. Information is stored in specific beta-sheet protein conformations that can act as cytoplasmic molecular memories. The conformational information can be transmitted to next generations in a non-nucleic acid based inheritance system utilizing the self-perpetuating potential of such beta-rich protein aggregates. Chaperones play a crucial role in the model by regulating and balancing the process of folding and misfolding; they also assist in preventing the development of aggregation-based disease. The protein conformation-mediated information system could represent an evolutionary conserved primordial mechanism: while the main strategy has been to ensure rapid folding of polypeptides into the native, functional conformation, the disfolded, beta-rich amyloidogenic state has provided advantage by providing a cytoplasmic, protease-resistant self-perpetuating DNA-independent adaptive inheritance system. The model offers an explanation for the problematic question of the evolution of complex behavioural traits and has even impact in the context of mammalian cloning: the protein conformation-based information localized in the somatic cytoplasm is lost when transferring nuclei only into enucleated oocytes. The protein conformation-based model presented herein postulates that proteins may contain much more information than determined by the nucleotide-triplet controlled peptide sequence and that there exists cross-talk and information exchange between proteins.

Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interleukin-1beta and interleukin-18.

OBJECTIVE: In amyloid A (AA) amyloidosis the receptor for advanced glycation end products is a target for the circulating amyloid precursor protein (SAA) resulting in upregulation of the proinflammatory cytokine pathway. Besides inducing hepatic SAA synthesis the interleukin-1 cytokine family is involved in the regulation of haematopoiesis. We therefore studied the relationship between the circulating levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), a new member of the IL-1 complex, as well as polymorphisms within the IL-1 cluster with the occurrence of anaemia in patients with AA amyloidosis. DESIGN, SETTING AND SUBJECTS: The study included 54 adult patients with biopsy-proven reactive amyloidosis allocated into three groups on the basis of haemoglobin (Hb) level: group I included all patients with Hb < 110 g L(-1) (n = 16); group II patients (Hb > 110 g L(-1), n = 16) were selected to match group I patients with respect to sex, age, underlying disease (seropositive, erosive rheumatoid arthritis) and renal function; and group III patients (n = 38) represented all patients (unselected) with Hb > or = 110 g L(-1). Gene polymorphisms were studied by polymerase chain reaction restriction length assay and included the base exchange at position-889 of the IL-1alpha gene, the polymorphic region at position-511 and the polymorphic locus at exon 5, position +3954 of the IL-1beta gene, as well as the IL-1 receptor antagonist (IL-1Ra) exon 2 polymorphism caused by the 86-bp tandem repeats. Plasma IL-1beta, IL-1alpha, IL-18, IL-1 Ra, SAA, ferritin, soluble transferrin receptor and erythropoietin levels were studied by enzyme immunoassays. RESULTS: Circulating IL-beta and IL-18 were significantly raised in the anaemic patients with AA amyloidosis when compared with group II patients (matched, Hb > 110 g L(-1)) as well as group III patients (nonmatched, Hb > or = 110 g L(-1)). A significant inverse relationship was found between IL-1beta and haemoglobin levels, as well as between IL-18 and haemoglobin levels. The frequency of allele 2 (T) of the IL-1beta-511 promoter gene was significantly increased and that of allele 1 (C) decreased in anaemic amyloid patients (group I) when compared with group II and III patients. Circulating IL-1beta levels tended to be higher amongst the IL-1beta-511 allele 2 carriers than amongst the noncarriers, as well as amongst the anaemic amyloid patients filling all criteria of anaemia of chronic disease. CONCLUSION: The occurrence of anaemia in patients with AA amyloidosis is associated with allele 2 (T) of the IL-1beta-511 promoter gene and elevated levels of circulating IL-1beta and IL-18. In AA amyloidosis the raised cytokine levels may generate a vicious cycle leading to accelerated amyloidogenesis, suppression of erythropoiesis and aggravation of the underlying inflammatory disorder.

Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis.

OBJECTIVE: To study tumor necrosis factor alpha (TNFalpha) -308 gene promoter polymorphism and circulating levels of TNFalpha and soluble TNF receptor type I (sTNFRI) in rheumatoid arthritis (RA) patients with and without reactive amyloidosis. METHODS: In a retrospective study, we examined 55 RA patients with biopsy-proven reactive amyloidosis and 55 control RA patients without amyloidosis (matched for age, sex, rheumatoid factor titer, and RA duration). Inflammatory activity was assessed by measuring the erythrocyte sedimentation rate and C-reactive protein level. TNFalpha gene promoter polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine and receptor levels were measured by enzyme-linked immunoassays. RESULTS: Patients with RA and amyloidosis had significantly higher TNFalpha and sTNFRI levels than did the control RA patients. The increased circulating levels of TNFalpha correlated with interleukin-18 levels, but not with the serum amyloid A protein levels or with TNFalpha -308 gene promoter polymorphism (reported to be associated with high TNFalpha levels and certain disease susceptibilities). In the patients with RA and amyloidosis, those with anemia had significantly higher TNFalpha and sTNFRI levels than did those without anemia, and circulating TNFalpha and sTNFRI levels correlated negatively with hemoglobin concentrations. In the patients with RA and amyloidosis, those with nephropathy had significantly higher TNFalpha and sTNFRI levels than did those without nephropathy; in patients with isolated proteinuria (but no creatinine elevation) the TNFalpha level was also significantly increased, indicating that the TNFalpha elevation was not merely a consequence of impaired renal function. CONCLUSION: This study shows that circulating levels of TNFalpha and sTNFRI are significantly increased in RA patients with amyloidosis as compared with control RA patients without amyloidosis and that the increased levels may be implicated in the pathogenesis of certain disease manifestations, including anemia of chronic disease and renal pathology in reactive amyloidosis.

Raised circulating interleukin-18 levels in reactive AA-amyloidosis.

OBJECTIVE: To study the circulating levels of interleukin-18 (IL-18), a proinflammtory cytokine implicated in the T helper I response, in patients with rheumatoid arthrtitis (RA) with or without amyloidosis. METHODS: Plasma IL-18 levels were studied by enzyme-linked immusorbent assay in 55 RA patients with reactive amyloidosis and in 55 RA patients without amyloidosis matched with respect to age, sex, seropositivity, disease duration and inflammatory activity, as well as in 55 healthy control subjects. RESULTS: Plasma IL-18 levels were significantly elevated in RA patients as compared with control subjects. Those RA patients who had amyloid had significantly higher circulating level of IL-18 than those without amyloid (418.1 +/- 32.1 ng/l versus 317.0 +/- 21.3 ng/l, P<0.02). This difference was not due to differences in inflammatory activity, nor was it related to renalfunction. CONCLUSION: RA is associated with increased levels of plasma IL-18, the levels being significantly higher in patients with amyloid than in those without amyloid The increased level in the amyloidosis patients may reflect the interaction ofamyloid with cellular meatbolic pathways or, possibly, suggest a direct role of IL-18 in amyloidogenesis.