Biochemistry. 2002 Sep 10;41(36):11017-24. Unusual property of prion protein unfolding in neutral salt solution.
Nandi PK, Leclerc E, Marc D.
Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France. nandours.inra.fr
The unfolding of cellular prion protein and its refolding to the scrapie isoform are related to prion diseases. Studies in the literature have shown that structures of proteins, either acidic or basic, are stabilized against denaturation by certain neutral salts, for example, sulfate and fluoride. Contrary to these observations, the full-length recombinant prion protein (amino acid residues 23-231) is denatured by these protein structure stabilizing salts. Under identical concentrations of salts, the structure of the sheep prion protein, which contains a greater number of glycine groups in the N-terminal unstructured segment than the mouse protein, becomes more destabilized. In contrast to the full-length protein, the C-terminal 121-231 prion protein fragment, consisting of all the structural elements of the protein, viz., three alpha-helices and two short beta-strands, is stabilized against denaturation by these salts. We suggest that an increase in the concentration of the anions on the surface of the prion protein molecule due to their preferential interaction with the glycine residues in the N-terminal segment destabilizes the structure of the prion protein by perturbing the prion helix 1 which is the most soluble of all the protein alpha-helices reported so far in the literature. The present results could be relevant to explain the observed structural conversion of the prion protein by anionic nucleic acids and sulfated glycosaminoglycans.
PMID:_12206674
Ann Neurol. 2002 Aug;52(2):195-204. Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Copper toxicity contributes to neuronal death in Wilson's disease and has been speculatively linked to the pathogenesis of Alzheimer's and prion diseases. We examined copper-induced neuronal death with the goal of developing neuroprotective strategies. Copper catalyzed an increase in hydroxyl radical generation in solution, and the addition of 20 microM copper for 22 hours to murine neocortical cell cultures induced a decrease in ATP levels and neuronal death without glial death. This selective neuronal death was associated with activation of caspase-3 and was reduced by free radical scavengers and Z-Val-Ala-Asp fluoromethylketone, consistent with free radical-mediated injury leading to apoptosis. Pyruvate dehydrogenase is especially vulnerable to inhibition by oxygen free radicals, and the upstream metabolites, pyruvate, phosphoenolpyruvate, and 2-phosphoglycerate were elevated in cortical cells after toxic exposure to copper. One approach to protecting pyruvate dehydrogenase from oxidative attack might be to enhance binding to cofactors. Addition of thiamine, dihydrolipoic acid, or pyruvate reduced copper-induced neuronal death. To test efficacy in vivo, we added 1% thiamine to the drinking water of Long Evans Cinnamon rats, an animal model of Wilson's disease. This thiamine therapy markedly extended life span from 6.0 +/- 1.6 months to greater than 16 months.
PMID:_12210790
Anim Biotechnol. 2002 May;13(1):159-62. Cloning and sequencing of quail and pigeon prion genes.
Zhang L, Li N, Wang QG, Fan BL, Meng QY, Wu CX.
Quail and pigeon PrP genes were cloned and sequenced. Like mammalian PrP genes, quail and pigeon genes are encoded by a single exon of a single copy gene in the genome. All of the structural features of mammalian PrP genes were found in the quail and pigeon PrP gene. Compared with the nucleotide sequences of mammalian PrP, they display generally 30% similarity. When compared with chicken PrP's DNA sequence, they show a higher homology (90%), and an even higher homology (99%) when compared to each other. A phylogenetic tree was constructed to trace the evolution of the prion gene in animals.
PMID:_12212939
po.cwru.edu
Prion diseases or transmissible spongiform encephalopathies, are neurodegenerative disorders that are genetic, sporadic, or infectious. The pathogenetic event common to all prion disorders is the conformational transformation of the cellular prion protein (PrP^C) to the scrapie form (PrP^Sc), that deposits in the brain parenchyma and induces neuronal death. Infectious prion disorders are caused by exogenously introduced PrP^Sc that acts as a template in the conversion of endogenous PrP^C to nascent PrP^Sc, and subsequently the process becomes autocatalytic. To understand the process of cellular uptake of PrP^Sc and its mechanism of cellular toxicity, previous studies have used a PrP fragment spanning residues 106-126 (PrP^Tx) that is toxic to primary neurons in culture, and mimics PrP^Sc in its biophysical properties [9,11,14]. Several possible mechanisms of cell death by PrP^Tx have been proposed [2,3,10,11,18], but the existing data are unclear. To identify the biochemical pathways of neurotoxicity by this fragment, we have isolated mutant neuroblastoma and NT-2 cells that are resistant to toxicity by PrP^Tx. We show that these cells bind and internalize PrP^Tx in a temperature dependent fashion, and the peptide accumulates in intracellular compartments, probably lysosomes, where it has an unusually long half-life. The PrP^Tx-resistant phenotype of the cells reported in this study could result from aberrant binding or internalization of the peptide, or due to an abnormality in the downstream pathway(s) of neuronal toxicity. The PrP^Tx-resistant cells are therefore a useful tool for evaluating the cellular and biochemical pathways that lead to cell death by this peptide, and will provide insight into the mechanism(s) of neurotoxicity by PrP^Sc.
PMID:_12214058 [PubMed - as supplied by publisher]
Hair loss is a problem of personal issues. Examining the factors of hair growth may
shed light on how hair loss might occur.
How long can hair grow before it stops growing eventually?
Given that the hair growth rate is quite uniform and constant, somewhere between 0.3-0.5 millimeters per day, it's believed that the length of anagen, the growth phase, differs among individuals, and this is the major determinant to the maximum hair length. For some individuals, anagen may last ten years. Of course the length of the anagen is governed by genes, and the genetic background of the individuals. Non-genetic factors such as nutritional condition, weather, seasonal changes (hair may grow a bit faster during winter), taking medications, health condition may of course influence the rate of
hair growth as well as hair loss.
The shape of the hair, straight or curly, is dependent on the shape of the follicle. A circular or round hair follicle would generate straight hair, while the follicle with oval or elliptical shapes (in its cross-section) would produce a curly hair.