How different prion variants lead to different disease patterns
Misfolded prion proteins are considered to trigger neurodegenerative diseases. Researchers from Heinrich Heine University Düsseldorf (HHU) and Forschungszentrum Jülich have found an explanation for why different forms of Creutzfeld-Jacob disease (CJD) are associated with different variants of the prion protein. In the Journal of Biological Chemistry, they show how the prion variants undergo different misfolding processes. (Source: Forschungszentrum Jülich – Press releases)
Prions are special proteins that are formed in the brain. Normally, they are harmless. If the prions occur in a fold that deviates from the natural form – that is, in a different three-dimensional form – the proteins can clump together, aggregating them. In addition, misfolded proteins can cause other prion proteins with correct folding to also refold. These misfolded proteins are associated with neurodegenerative diseases such as Creutzfeld-Jacob disease in humans, BSE in cattle, and scrapie in sheep.
Copyright: HHU / Thomas Pauly and Najoua Bolakhrif
In humans, there are two natural variants of the prion protein that differ only in a different amino acid (methionine, Met for short, or valine, Val for short). Two variants of Creutzfeld-Jacob disease are also related to these variants. Until now, there has been no explanation of how a different amino acid can influence the clinical picture of CJD.
A team led by first authors Thomas Pauly and Najoua Bolakhrif from the Institute of Physical Biology at HHU and the Institute of Biological Information Processes – Structural Biochemistry at Forschungszentrum Jülich (each led by Prof. Dr. Dieter Willbold) has now shown for the first time that the two prion variants behave differently at the molecular level. The researchers discovered that the different prion variants undergo different misfolding processes.
While the Val variant aggregates directly, the Met variant, which is more common in the human population, requires an intermediate step to do so, in which smaller aggregates are first formed. “The finding that the neurotoxic aggregates are formed by different pathways may contribute to the understanding of the different disease patterns,” Pauly and Bolakhrif emphasize.
In addition to the institutes led by Prof. Willbold, the Institute of Pharmaceutical and Medicinal Chemistry at HHU (Head: Prof. Dr. Holger Gohlke) was also involved in the study, which has now been published in the Journal of Biological Chemistry. Prof. Gohlke and his colleague Jesko Kaiser carried out molecular dynamics simulations with which they determined interactions at the atomic level that explain the different stabilities of the two variants.
The original press release can be found at:
Wie unterschiedliche Prionenvarianten zu unterschiedlichen Krankheitsbildern führen (only in german)
The original publication can be found at:
Thomas Pauly, Najoua Bolakhrif, Jesko Kaiser, Luitgard Nagel-Steger, Lothar Gremer, Holger Gohlke, Dieter Willbold, Met/Val129 polymorphism of the full-length human prion protein dictates distinct pathways of amyloid formation, Journal of Biological Chemistry (2022), 28. August 2022, DOI: 10.1016/j.jbc.2022.102430
Localization in the Helmholtz Research Field Information:
Helmholtz-Forschungsbereich Information, Programm 2: Natural, Artificial and Cognitive Information Processing, Topic 4: Molecular and Celullar Information
Contact:
Prof. Dr. Dieter Willbold
Institute of Biological Information processing (IBI)
Structural Biochemistry (IBI-7)
Forschungszentrum Jülich
Phone: +49 2461 61-2100
E-Mail: d.willbold@fz-juelich.de
Prof. Dr. Holger Gohlke
Institut für Biologische Informationsprozesse (IBI)
Bioinformatics (IBI-4)
Forschungszentrum Jülich
Phone: +49 2461 61-85550
E-Mail: h.gohlke@fz-juelich.de
Thomas Pauly
Institute of Biological Information processing (IBI)
Structural Biochemistry (IBI-7)
Forschungszentrum Jülich
Phone: +49 2461 61-9448
E-Mail: t.pauly@fz-juelich.de
Najoua Bolakhrif
Institute of Biological Information processing (IBI)
Structural Biochemistry (IBI-7)
Phone: +49 2461 61-9390
E-Mail: n.bolakhrif@fz-juelich.de
Contact for this press release:
Dr. Regine Panknin
Press Officer
Forschungszentrum Jülich
Phone: +49 2461 61-9054
E-Mail: r.panknin@fz-juelich.de
