NR AXTE
AU Mouthon,F.; Charveriat,M.; Correia,E.; Iris,F.; Deslys,J.P.
TI Could Alterations in Neuroglial Connections Explain Rapid Progression of Late Clinical Phase?
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.117
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Neuropathogenesis of Prion diseases involves, on the one hand, the Prion protein itself and, on the other hand, neurons, astrocytes and microglial cells, by molecular mechanisms that remain poorly understood. To investigate these mechanisms, we used an integrative biology approach based upon information from public databases and specific data about Prion diseases to develop a theoretical model of Prion neuropathogenesis. Our first model describes successive molecular alterations leading to vicious circles that corrupt physiological stability.
To evaluate the neuropathological mechanisms predicted by this theoretical model, we used two complementary experimental approaches, based on the study of gene expression modifications and on immunohistochemical localization. As predicted by the model, these parameters appear to disorganize membrane-associated cytoskeleton components at an early stage of infection in the neurons, and at a later stage in activated astrocytes.
The implementation of experimental observations in an integrative biological algorithm, led to a new predictive model that describes a major alteration of intercellular connections notably concerning glial cells. Histological evaluations confirm a dramatic increase of neuroglial connections that form an interconnected network near PrPres accumulation brain locations. By using Electroencephalographic (EEG) investigation in infected mice, we demonstrate functional alterations of cerebral activities correlated with the increase of neuroglial connections.
Thus, our results based on convergence between a theoretical approach and experimental observations show for the first time functional alterations of neuroglial connections which could lead, by toxic bystander effect, to the unexplained rapid aggravation of the clinical late phase. Neuroglial connections constitute an original target that could be applied to other neurologic disorders.
AD F. Mouthon, M. Charveriat, E. Correia, J.P. Deslys, CEA/DSV/IMETI/SEPIA, France; F. Iris, Bio-Modeling Systems SAS, France
SP englisch
PO Schottland