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Abnormal Conformation (abnormal + conformation)
Selected AbstractsQuantitative isolation of ,1AT mutant Z protein polymers from human and mouse livers and the effect of heat,HEPATOLOGY, Issue 1 2005Jae-Koo An Alpha-1-antitrypsin (,1AT) deficiency in its most common form is caused by homozygosity for the ,1AT mutant Z gene. This gene encodes a mutant Z secretory protein, primarily synthesized in the liver, that assumes an abnormal conformation and accumulates within hepatocytes causing liver cell injury. Studies have shown that mutant ,1ATZ protein molecules form unique protein polymers. These Z protein polymers have been hypothesized to play a critical role in the pathophysiology of liver injury in this disease, although a lack of quantitative methods to isolate the polymers from whole liver has hampered further analysis. In this study, we demonstrate a quantitative ,1ATZ polymer isolation technique from whole liver and show that the hepatocellular periodic acid-Schiff,positive globular inclusions that are the histopathological hallmark of this disease are composed almost entirely of the polymerized ,1ATZ protein. Furthermore, we examine the previously proposed but untested hypothesis that induction of ,1ATZ polymerization by the heat of physiological fever is part of the mechanism of hepatic ,1ATZ protein accumulation. The results, however, show that fever-range temperature elevations have no detectable effect on steady-state levels of intrahepatic Z protein polymer in a model in vivo system. In conclusion, methods to separate insoluble protein aggregates from liver can be used for quantitative isolation of ,1ATZ protein polymers, and the effect of heat from physiological fever may be different in vivo compared with in vitro systems. (HEPATOLOGY 2005;41:160,167.) [source] Tau oligomers and aggregation in Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 6 2010Marco A. Meraz-Ríos J. Neurochem. (2010) 112, 1353,1367. Abstract We are analyzing the physiological function of Tau protein and its abnormal pathological behavior when this protein is self-assemble into pathological filaments. These aggregates of Tau protein are the main components in many diseases such as Alzheimer's disease (AD). Recent studies suggest that Tau acquires complex oligomeric conformations which may be toxic. In this review, we emphasized the possible phenomena implicated in the formation of these oligomers. Studies with chemical inductors indicates that the microtubule-binding domain is the most important region involved in Tau aggregation and showed the requirement of a pre-arrange Tau in abnormal conformation to promote self-assembly. Transgenic animal models and AD neuropathology studies showed that post-translational modifications are also implicated in Tau aggregation and neural cell death during AD development. Therefore, we analyzed some events that could be present during Tau aggregation. Finally, we included a brief discussion of the possible relation between glucose metabolism dysfunction in AD, and data of Tau aggregation by using aggregation inhibitors. In conclusion, the process Tau aggregation deserves further investigations to design possible therapeutic targets to inhibit the toxicity of these aggregates and it is possible that could be extended to other diseases with similar etiology. [source] Neurotoxic species in prion disease: a role for PrP isoforms?JOURNAL OF NEUROCHEMISTRY, Issue 5 2007Christopher F. Harrison Abstract Prion diseases such as bovine spongiform encephalopathy in cattle and Creutzfeldt,Jakob disease in humans are associated with the misfolding and accumulation of an abnormal conformation of the host-encoded prion protein (PrP). Despite intensive research efforts conducted on PrP, the toxic agent involved in neurodegeneration is as yet unidentified. Several potential candidates have been proposed, each of which may be relevant to subsets of the broad array of prion diseases. In this study, we review current knowledge on neurotoxic PrP species, including the importance of a central hydrophobic domain for mediating neurotoxicty. [source] Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosisJOURNAL OF NEUROCHEMISTRY, Issue 5 2002Makoto Urushitani Abstract Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS. [source] Vaccination as a Therapeutic Approach to Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Thomas Wisniewski MD Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [source] Toward an Understanding of Polyglutamine NeurodegenerationBRAIN PATHOLOGY, Issue 2 2000Henry L. Paulson Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The polyglutamine expansion diseases identified so far are slowly progressive disorders in which distinct yet overlapping brain regions are selectively vulnerable to degeneration. Despite their clinical differences these diseases likely share a common pathogenic mechanism, occurring at the protein level and centered on an abnormal conformation of expanded polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of polyglutamine disease, but still there are many unanswered questions. In this review, I first outline some of the shared features of polyglutamine diseases and then discuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity. [source] | ||||||||||