Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):1-10. Insoluble TATA-binding protein accumulation in Huntington's disease cortex.
van Roon-Mom WM, Reid SJ, Jones AL, MacDonald ME, Faull RL, Snell RG.
Division of Anatomy with Radiology, Faculty of Medicine and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Huntington's disease is a dominantly inherited neurological disorder where specific neurodegeneration is caused by an extended polyglutamine stretch in the huntingtin protein. Proteins with expanded polyglutamine regions have the ability to self-aggregate and previous work in our laboratory, and by others, revealed sparse amyloid-like deposits in the Huntington's disease brain, supporting the hypothesis that the polyglutamine stretches may fold into regular beta-sheet structures. This process of folding has similarities to other neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and the prion diseases which all exhibit beta-sheet protein accumulation. We were therefore interested in testing the hypothesis that TATA-binding protein may play a role in Huntington's disease as it contains an elongated polymorphic polyglutamine stretch that ranges in size from 26 to 42 amino acids in normal individuals. A proportion of TBP alleles fall within the range of glutamine length that causes neurodegeneration when located in the huntingtin protein. In this study the distribution and cellular localisation of TATA-binding protein was compared to the distribution and cellular localisation of the huntingtin protein in the middle frontal gyrus of Huntington's disease and neurologically normal subjects. Seven different morphological forms of TATA-binding protein-positive structures were detected in Huntington's disease but not in control brain. TATA-binding protein labelling was relatively more abundant than huntingtin labelling and increased with the grade of the disease. At least a proportion of this accumulated TBP exists as insoluble protein. This suggests that TBP may play a role in the disease process.
PMID:_12531510
J Biol Chem. 2003 Feb 7;278(6):3726-34. Epub 2002 Nov 12. Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein.
Nunziante M, Gilch S, Schatzl HM.
Gene Center Munich, Max von Pettenkofer Institute for Virology, Faculty of Medicine, Ludwig-Maximilians-University, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany.
Aberrant metabolism and conformational alterations of the cellular prion protein (PrP(c)) are the underlying causes of transmissible spongiform encephalopathies in humans and animals. In cells, PrP(c) is modified post-translationally and transported along the secretory pathway to the plasma membrane, where it is attached to the cell surface by a glycosylphosphatidylinositol anchor. In surface biotinylation assays we observed that deletions within the unstructured N terminus of murine PrP(c) led to a significant reduction of internalization of PrP after transfection of murine neuroblastoma cells. Truncation of the entire N terminus most significantly inhibited internalization of PrP(c). The same deletions caused a significant prolongation of cellular half-life of PrP(c) and a delay in the transport through the secretory pathway to the cell surface. There was no difference in the glycosylation kinetics, indicating that all PrP constructs equally passed endoplasmic reticulum-based cellular quality control. Addition of the N terminus of the Xenopus laevis PrP, which does not encode a copper-binding repeat element, to N-terminally truncated mouse PrP restored the wild type phenotype. These results provide deeper insight into the life cycle of the PrP(c), raising the novel possibility of a targeting function of its N-proximal part by interacting with the secretory and the endocytic machinery. They also indicate the conservation of this targeting property in evolution.
PMID:_12431994
Nature. 2000 Nov 23;408(6811):479-83. Binding of disease-associated prion protein to plasminogen.
Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A.
Institute for Neuropatholgy, University Hospital of Zurich, Switzerland.
Transmissible spongiform encephalopathies are associated with accumulation of PrP(Sc), a conformer of a cellular protein called PrP(C). PrP(Sc) is thought to replicate by imparting its conformation onto PrP(C) (ref. 1), yet conformational discrimination between PrP(C) and PrP(Sc) has remained elusive. Because deposition of PrP(Sc) alone is not enough to cause neuropathology, PrP(Sc) probably damages the brain by interacting with other cellular constituents. Here we find activities in human and mouse blood which bind PrP(Sc) and prion infectivity, but not PrP(C). We identify plasminogen, a pro-protease implicated in neuronal excitotoxicity, as a PrP(Sc)-binding protein. Binding is abolished if the conformation of PrP(Sc) is disrupted by 6M urea or guanidine. The isolated lysine binding site 1 of plasminogen (kringles I-III) retains this binding activity, and binding can be competed for with lysine. Therefore, plasminogen represents the first endogenous factor discriminating between normal and pathological prion protein. This unexpected property may be exploited for diagnostic purposes.
PMID:_11100730
Cell Mol Neurobiol. 2000 Dec;20(6):717-30. Early appearance but lagged accumulation of detergent-insoluble prion protein in the brains of mice inoculated with a mouse-adapted Creutzfeldt-Jakob disease agent.
Nakaoke R, Sakaguchi S, Atarashi R, Nishida N, Arima K, Shigematsu K, Katamine S.
Department of Bacteriology, Nagasaki University School of Medicine, Japan.
1. To elucidate mechanisms for the generation of the detergent-insoluble, proteinase K-resistant prion protein (PrP(Sc)) from the detergent-soluble, proteinase K-sensitive PrP (PrP(C)) and the replication of the infectious agent in prion diseases, we followed the kinetics of detergent-insoluble PrP and PrP(Sc) levels, infectious titers, and associated pathological changes in the brains of mice inoculated with a mouse-adapted Creutzfeldt Jakob disease agent. 2. PrP(Sc) in brain homogenate and detergent-insoluble PrP enriched by two-cycle ultracentrifugation were detected by immunoblotting and their relative amounts were estimated according to a standard curve plotted between the amount of PrP and signal intensity on immunoblotting. The titer of infectivity was determined by the incubation periods of mice inoculated with the unfractionated homogenate on the basis of a standard curve plotted between the titer and incubation period. 3. Detergent-insoluble PrP became detectable 4 weeks postinoculation (p.i.) well before the detection of PrP(Sc). The low level of detergent-insoluble PrP continued until dramatic accumulation occurred at 14 weeks p.i., correlating well with the accumulation of PrP(Sc) and development of pathological changes. The infectious titer was undetectable at 4 weeks p.i. and its logarithmic increase occurred 10 weeks p.i. preceding the logarithmic accumulation of PrPs. 4. The lag time of detergent-insoluble PrP accumulation and the discrepancy between infectious titers and PrPs observed during the early period after inoculation suggest a slow and rate-limiting step for the detergent-insoluble PrP to become the infectious agent-associated PrP(Sc).
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