Prion diseases can be sporadic, inherited and infectious. The vast majority (85 percent) of prion diseases in humans can be attributed to a spontaneous structural conversion of the cellular prion protein: Originally dominated by alpha-helices as structural elements, the prion protein is transformed into its misfolded "scrapie" isoform which is dominated by accordion-like folded protein sheets, so called beta-sheets. This changes its chemical properties: The molecule becomes less water-soluble and has a strong aggregation tendency.
"Once there is a misfolded and aggregated prion protein present in the tissue, a chain reaction is triggered where one protein after another changes its shape, like dominos knocking over each other", says Professor Armin Giese (Center for Neuropathology and Prion Research, LMU Munich). The initial event in this misfolding cascade was so far widely unknown. Now the scientists have identified an oxidation within the prion protein as the cause of the structural conversion: "Although other mechanisms are also discussed, we are convinced that the oxidation of the amino acid methionine within the prion protein plays a key role", reports PD Dr. Nediljko Budisa, the head of the research group "Molecular Biotechnology"at the Max Planck Institute.
While the hydrophobic methionine usually stabilizes alpha-helices effectively, its oxidized form supports the structural conversion into beta-sheets. If the oxidative stress within the cell is sufficient enough to oxidise certain methionine molecules within the prion protein, an irreversible process with serious consequences starts: "The prion protein gets literally pushed apart because of the oxidation", says Budisa, "obviously this is devastating for the folding".
To prove these findings conclusively the scientists used an elegant trick: The methionine molecules were replaced with isosteric, chemically stable, non-oxidizable analogs, i.e. with the more hydrophobic norleucine (simulates non-oxidized methionine) and the highly hydrophilic methoxinine (simulates oxidized methionine). "In this way, we created artificial prion proteins, which, like Yin and Yang, reflect two extreme conditions: One prion, that contains non-oxidized methionine molecules only, and one in which all methionine molecules are oxidized", explains Budisa. The norleucine variant resulted in an alpha-helix rich protein that lacks the in vitro aggregation protein of the parent protein. In contrast, the methoxinine variant resulted in a beta-sheet rich protein with strong aggregation tendency.
These results support a correlation of oxidative stress in cells and the misfolding of proteins. They are highly relevant not only for prion research, but also for other neurodegenerative diseases that are associated with protein misfolding. Research in this field is of general importance, because it can give new insights in neurodegenerative diseases and help with the development of new therapeutic strategies.Original publication:
Dr. Monika Gödde | idw
Further reports about: > Creutzfeldt-Jakob Disease > LMU > Oxidation > alpha-helices > alpha-helix rich protein > amino acid methionine > beta-sheets > cellular prion protein > degenerative diseases > highly hydrophilic methoxinine > hydrophobic norleucine > methionine molecules > misfolded "scrapie" isoform > neurodegenerative disease > non-oxidizable analogs > oxidative stress > prion diseases > prion protein > simulates non-oxidized methionine > simulates oxidized methionine > structural change of human prion proteins
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering