1,721,189 research outputs found
Amyloidogenesis in its biological environment: challenging a fundamental issue in protein misfolding diseases.
Full text linkThe inability of a protein to adopt its native and soluble conformation (protein misfolding) is the origin of an increasing number of human diseases. The misfolding of a protein is often associated with its assembly into extracellular fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterise amyloid formation in vitro, it is increasingly evident that the biological environment in which aggregation occurs naturally influences the mechanism and rate of the process, as well as the structure and stability of the resulting fibrils. This problem is not trivial because of the inherent complexity of biology and difficulty to design proper experiments able to address the molecular level of the phenomenon in vivo. We will show successful approaches that have been used recently and will illustrate some of the results that have contributed to elucidate important structural aspects of amyloid formation in vivo
Current concepts on the pathogenisis of systemic amyloidosis
No full textAmyloidosis is a pathological condition in which protein is deposited extracellularly in the form of insoluble fibrils that lead to organ dysfunction and death. Many different types of proteins are known to form amyloid and cause a heterogeneous array of clinical conditions. The unifying aspect of these conditions is the common structural entity resulting from the assembly of a primarily beta-structure protein into 5-10 nm wide non-branching insoluble fibrils displaying the characteristic green birefringence of bound Congo red dye when viewed under polarized light. Several factors contribute to amyloid assembly. Certain biophysical characteristics of the amyloidogenic precursor influence amyloidogenicity. Any mutation that sufficiently decreases protein stability favours the formation of a partially folded state under physiological conditions. This intermediate exposes other key sequence elements to the solvent, i.e. hydrophobic or charged residues that decrease solubility and promote aggregation and ultimately amyloid formation. In addition to primary protein structure, which confers a susceptibility to amyloid formation, other elements are probably important for the initiation, development and persistence of amyloid deposits: proteoglycans, amyloid P component, apolipoprotein E and others, most of which are normal constituents of basement membranes. The role of these factors in amyloidogenesis has been studied in two major systemic amyloidoses with prominent renal involvement: light-chain and beta-2-microglobulin amyloidosis. A detailed understanding of the molecular processes leading to amyloid deposition is required for the development of effective therapies
Towards understanding the molecular pathogenesis of monoclonal immunoglobulin light-chain deposition
No full textLysozyme: A paradigmatic molecule for the investigation of protein structure, function and misfolding
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Immunoglobulin light chain amyloidosis--the archetype of structural and pathogenic variability.
No full textAL amyloidosis is caused by deposition in target tissue of amyloid fibrils constituted by monoclonal immunoglobulin light chains. The amyloidogenic plasma cells derive from a transformed memory B cell that can be identified by anti-idiotype monoclonal antibodies. Comparison of the primary structures of amyloidogenic and nonamyloidogenic light chains does not show any common structural motif in the amyloidogenic variants but reveals peculiar replacements which can destabilize the folding state. Reduced folding stability now appears to be a unifying property of amyloidogenic light chains. The tendency of these proteins to populate a partially unfolded intermediate state is a key event in the self-association that progresses to the formation of oligomers and fibrils. The mechanism of organ damage caused by AL amyloid deposition is not known, but clinical findings suggest that the process of amyloid fibril formation itself exerts tissue toxic effects independently of the amount of amyloid deposited. Since the disease is caused by the neoplastic expansion of the plasma cell population synthesizing the amyloidogenic light chains, the clone represents the prime therapeutic target of conventional chemotherapy and experimental immunotherapy. In common with other types of amyloidosis the therapeutic strategy can take advantage of drugs able to improve the reabsorption of the amyloid deposits or able to bind and stabilize the light chain in the native-like folded state
Systemic amyloidosis: lessons from β2-microglobulin.
Full text linkβ2-Microglobulin is responsible for systemic amyloidosis affecting patients undergoing long-term hemodialysis. Its genetic variant D76N causes a very rare form of familial systemic amyloidosis. These two types of amyloidoses differ significantly in terms of the tissue localization of deposits and for major pathological features. Considering how the amyloidogenesis of the β2-microglobulin mechanism has been scrutinized in depth for the last three decades, the comparative analysis of molecular and pathological properties of wild type β2-microglobulin and of the D76N variant offers a unique opportunity to critically reconsider the current understanding of the relation between the protein's structural properties and its pathologic behavior
Nanotechnology drives a paradigm shift on protein misfolding diseases and amyloidosis
Full text linkIn almost a century of scientific work on the mechanism of amyloid diseases much of the attention has been focused on the amyloid fibrils, which still represent the diagnostic hallmark of the disease and are easily identified in affected organs for their peculiar tinctorial properties and the fibrillar shape. However, it has been lately discovered that the seeds of the pathogenesis are deeply hidden in the structure and folding dynamics of proteins at the monomeric state which almost indistinguishable from the normal counterpart through classical biochemical approaches. In the recent years soluble oligomeric/prefibrillar species, putatively cytotoxic, were discovered and even more recently polymorphisms of shape and structure of fibrils was emerging as a property that could dictate the bioactivity of amyloid as well as the specificity of its tissue localization. Nanotechnology through the biophysical analysis of the single molecules (monomers or oligomers or fibrils) is the propulsive disciplines in the transformation of our knowledge on the molecular mechanism of this disease. It will provide, in the forthcoming years, precious analytical devices mimicking the biological microenvironment where the molecular events causing the amyloid formation will be monitored and possibly modulated in a real time frame
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