Prion (protéine) | EPFL Graph Search

Le est un type de protéine naturellement présent dans l'organisme dans sa forme cellulaire (PrPC) susceptible de donner une forme pathogène PrPSc par une mauvaise conformation ou repliement. Cette forme pathogène est capable de transmettre cette forme mal repliée à des variantes normales de la même protéine. Ces prions dits pathogènes caractérisent plusieurs maladies neurodégénératives mortelles et transmissibles chez l'homme et de nombreux autres animaux. On ignore encore ce qui cause le mauvais repliement de la protéine normale, mais la structure tridimensionnelle anormale est soupçonnée de conférer des propriétés infectieuses, en reconfigurant les molécules de protéines voisines dans la même forme. Le rôle infectieux d'une protéine contraste avec tous les autres agents infectieux connus tels que les viroïdes, les virus, les bactéries, les champignons et les parasites, qui eux contiennent tous des acides nucléiques (ADN, ARN ou les deux comme support de l’information infectieuse).

Characterisation of Living Matter Using Advanced Spectroscopy Techniques

Markus Bonda

In the context of an ageing society neurodegenerative disease have become more and more frequent among humans. Opposing the benefits of a longer life, these diseases have thus triggered research on neurons and how they interact with each other. In vitro as well as in vivo experiments are comparably involved. Due to the complex mechanisms occurring at the neuronal level there is a need for developing suitable techniques. Such techniques are required to provide high resolution in several respects in order to track cellular properties: Fourier transform infrared spectroscopy (FTIR) along with high-brilliance synchrotron radiation matches the requirements of high spectral and spatial resolution for chemical distinction perfectly. We have investigated a rat model of Huntington's disease (HD) with synchrotron-assisted Fourier transform infrared microspectroscopy (SIRMS). Several neurodegenerative diseases, ranging from Alzheimer's to prion disease, have now been identified to be caused by proteins which auto-assemble into high molecular weight amyloid aggregates or fibrils. HD is related to abnormal polyglutamine (polyQ) repeats. Its symptoms are progressive deterioration of cognitive and motor functions, along with extensive loss of neurons. In our model, one brain hemisphere was infected with HD while keeping the second one as a control. The two types of matter in the striatum are affected in different manners: in neuron-rich gray matter exposed to the disease, a higher content of aggregated protein is detected, but no signs of cell death. In contrast, myelin-rich white matter did not show any aggregates, but surprisingly showed a significant increase in phosphorylation. We interpret this result as the activation of the cellular response to stress which leads in the end to cell death. The drastic changes in the white matter were detected in the case of multiple sclerosis. We have studied its animal model, the experimental autoimmune encephalomyelitis (EAE). EAE is characterized by heavy loss of the insulating lipid-layer, the myelin around axons. This has been clearly confirmed by SIRMS and FTIR. Analysis of spatially resolved maps by both unsupervised principal component analysis and chemical signatures showed additional features of EAE. Both studies indicate that SIRMS is a powerful tool of detecting complex chemical processes in biological tissue in a relatively easy way. In addition to nanometer spatial resolution, the photonic force microscope (PFM) provides microsecond temporal resolution. A PFM tracks the Brownian motion of micron-sized beads embedded in solutions. Thanks to the high resolutions, we can calculate velocity auto-correlation functions (vacf) of the beads that are extremely sensitive on the short-time scale. We found that they depend in solutions containing polymers on the mesh size. The narrower the polymer mesh size, the earlier perturbations occur in the bead's motion. Polymer solutions possess a very interesting feature which is their viscoelasticity. Based on the mean square displacements of the beads, the complex shear modulus is obtained describing in a frequency-dependent manner viscosity and elasticity. In this way we could distinguish different polymers and also a pathologically relevant fibril: α-synuclein involved in Parkinson's disease.

EPFL2011

Trans‐seeding of Alzheimer‐related tau protein by a yeast prion

Zhiva Skachokova, Henning Paul-Julius Stahlberg

Abnormal tau protein aggregates constitute a hallmark of Alzheimer's disease. The mechanisms underlying the initiation of tau aggregation in sporadic neurodegeneration remain unclear. Here we investigate whether a non-human prion can seed tau aggregation. Due to their structural similarity with tau aggregates, we chose Sup35NM yeast prion domain fibrils for explorative tau seedings. Upon in vitro incubation with tau monomers, Sup35NM fibrils promoted the formation of morphologically distinct tau fibril strains. In vivo, intrahippocampal inoculation of Sup35NM fibrils accentuated tau pathology in P301S tau transgenic mice. Thus, our results provide first in vivo evidence for heterotypic cross-species seeding of a neurodegenerative human prion-like protein by a yeast prion. This opens up the conceptual perspective that non-mammalian prions present in the human microbiome could be involved in the initiation of protein misfolding in neurodegenerative disorders, a mechanism for which we propose the term “trans-seeding.”

2022

Characterisation of Living Matter Using Advanced Spectroscopy Techniques

Markus Bonda

EPFL2011