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Recent work has shown the proteins considered to be completely harmless can generate misfolded intermediates that aggregate to produce pre-fibril structures that are toxic to cells. Similar results were seen with dimers and trimers (prefibril states) of the amyloid-b peptide released from cultured neurons.
A diverse group of proteins that do not share significant secondary or tertiary structure can form amyloid-like protein aggregates. Even though their monomer forms share little in common, the insoluble amyloid aggregates have a common structure in which the monomer in the aggregates has significant b-structure whose strands run perpendicular to the aggregate axis. Since it has recently been shown that almost any protein, under the "right" set of conditions can form such aggregates, the stabilizing feature of protein aggregates must be potentially found in any protein. Evidence suggests that is the presence of a polypeptide backbone, which can form stable interstrand H-bonds in beta secondary structure, and not the side-chains, that is the source of the common amyloid structure. In contrast, native, nonamyloid forms of normal proteins must arise through specific interactions of unique side chain sequence and structure, which out competes nonspecific interactions among backbone atoms found in amyloid structures. Nonspecific aggregation becomes more prevalent when buried hydrophobic side chains and buried main chain atoms become more solvent exposed. Such exposure occurs when native proteins form intermediate molten globule states when subjected to altered solvent conditions or when destabilizing mutants of the wild-type protein arise. Some mutations may alter the cooperativity of folding which would increases the fraction of nonnative proteins states. Other mutations that decrease the charge on the protein or increasing their hydrophobicity might enhance aggregation. In addition, chemical modifications to proteins (such as oxidation or deamination) might destabilize the native state, leading to the formation of the molten globule state. Once formed, this state may aggregate through sequestering exposed side chain hydrophobes or through inter-main chain H bond formation. Aggregate formation appears to proceed through the initial formation of soluble units (which may or not be more toxic to cells than the final aggregate). Aggregates are kinetically stable species. Since amyloid aggregates are cytotoxic and almost any protein can form them, albeit with different propensities, nature, through evolutionary selection, has presumably disfavored proteins with high tendencies to form such aggregates.
- Nature Insights: Protein Folding and Misfolding (2003) - Great series of articles (PDFs).
Wasmer et al have determined a solid state NMR structure of an amyloid fiber state for a prion forming domain of the HET-s protein from the fungus P. anserina. It consists of a left-handed b solenoid.
Jmol: Amyloid Fibril Models from UCLA
Clearly accurate protein folding is required for cell viability. Aberrant protein folding clearly can be the cause of serious illness. Given the extraordinary nature of the task and its failure, the process governing protein folding must be highly regulated. The diagram below shows the steps that determine intracellular concentrations and locations of normal and aberrant protein structures.
Potential therapies of diseases of proteostasis include replacing aberrant proteins, shifting the equilibria toward active forms with small ligands, or modulating the pathways with agents that influence pathways such as signal transduction, transcription, translation, degradation, and translocation using molecules like siRNAs to modulate concentrations of chaperons, disaggregases, and signal pathways.
Biology of Serpins
Olivia S. Long , . Stephen C. Pak , in Methods in Enzymology , 2011
Protein misfolding , polymerization, and/or aggregation are hallmarks of serpinopathies and many other human genetic disorders including Alzheimer's, Huntington's, and Parkinson's disease. While higher organism models have helped shape our understanding of these diseases, simpler model systems, like Caenorhabditis elegans, offer great versatility for elucidating complex genetic mechanisms underlying these diseases. Moreover, recent advances in automated high-throughput methodologies have promoted C. elegans as a useful tool for drug discovery. In this chapter, we describe how one could model serpinopathies in C. elegans and how one could exploit this model to identify small molecule compounds that can be developed into effective therapeutic drugs.
Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells
Misfolding and aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases including Parkinson's disease (PD). Analyses of post mortem tissues revealed the presence of molecular chaperones within α-syn aggregates, suggesting that chaperones play a role in α-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates α-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against α-syn-induced toxicity. In this study, we investigated the effect of carbenoxolone (CBX), a glycyrrhizic acid derivative previously reported to upregulate Hsp70, in human neuroglioma cells overexpressing α-syn. We report that CBX treatment lowers α-syn aggregation and prevents α-syn-induced cytotoxicity. We demonstrate further that Hsp70 induction by CBX arises from activation of heat shock factor 1 (HSF1). The Hsp70 inhibitor MAL3-101 and the Hsp70 enhancer 115-7c led to an increase or decrease in α-syn aggregation, respectively, in agreement with these findings. In summary, this study provides a proof-of-principle demonstration that chemical modulation of the Hsp70 machine is a promising strategy to prevent α-syn aggregation.
CBX decreases α -syn-containing aggregates…
CBX decreases α -syn-containing aggregates and reduces total protein aggregation in H4/ α…
CBX induces Hsp70 expression in…
CBX induces Hsp70 expression in H4/ α -syn-GFP cells. (a) Relative mRNA expression…
Inhibition of Hsp70 causes α…
Inhibition of Hsp70 causes α -syn aggregation in H4/ α -syn-GFP cells treated…
Activation of Hsp70 reduces α…
Activation of Hsp70 reduces α -syn aggregation in H4/ α -syn-GFP cells treated…
HSF1 is activated in H4/ α -syn-GFP cells treated with CBX. (a) H4/…
CBX induces the generation of…
CBX induces the generation of intracellular ROS but does not induce apoptosis in…
Protein folding alterations in amyotrophic lateral sclerosis
Protein misfolding leads to the formation of aggregated proteins and protein inclusions, which are associated with synaptic loss and neuronal death in neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord. Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72. Chaperone proteins, including heat shock proteins (Hsp׳s) and the protein disulphide isomerase (PDI) family, assist in protein folding and therefore can prevent protein misfolding, and have been implicated as being protective in ALS. In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention. This article is part of a Special Issue entitled SI:ER stress.
Keywords: Amyotrophic lateral sclerosis C9ORF72 Disulphide bonds ER stress FUS Protein disulphide isomerase (PDI) Protein misfolding Superoxide dismutase 1 (SOD1) TDP-43.
Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution
The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca 2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.
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Chemical Biology of Neurodegeneration : A Molecular Approach
Written by an experienced neurochemist, this book focuses on the main actors involved in neurodegenerative disorders at a molecular level, and places special emphasis on structural aspects and modes of action. Drawing on recent data on enzyme structure, mode of action, and inhibitor design, it describes?from a biochemical point of view?the six most important neurotransmitter systems and their constituent enzymes and receptors. Misfolding and aggregation of proteins within the brain is also covered. In addition, the book surveys a wide range of proven and prospective therapeutic agents that modulate key processes in the brain, from their chemical synthesis to their mode of action in model systems as well as in the patient.
Chemical Biology of Neurodegeneration: A Molecular Approach is presented in two parts. The first introduces the neurotransmitter systems and provides a general explanation of the synapse and a description of the main structures involved in neurotransmission that can be considered therapeutic targets for disorders of the central nervous system. The second part presents molecular and chemical aspects directly involved or affected in neurodegeneration, including the metabolism of neurotransmitters, enzymes processing neurotransmitters, protein misfolding, and therapeutic agents.
-Uses an interdisciplinary approach to bridge the gap between the basic biochemical events in a nerve cell and their neurological effects on the brain
-Places emphasis on the chemistry of small molecule modulators that are potential lead molecules for new drugs
-Covers six key neurotransmitter systems and their enzymes and receptors?dopaminergic, noradrenergic, serotonergic, cholinergic, GABAergic, and glutamatergic
Chemical Biology of Neurodegeneration: A Molecular Approach is a key resource for medicinal chemists, neurobiologists, neurochemists, biochemists, molecular biologists, and neurophysiologists.
Pedro Merino, PhD, holds the Chair in Organic Chemistry at the University of Zaragoza, Spain. His scientific work has been presented in more than 220 papers, various book chapters, and one book. His research interests include chemical biology with particular focus on glycoscience, computational chemistry, asymmetric synthesis and catalysis.