Dr Chiara ZURZOLO (Membrane Trafficking and Pathogenesis Unit, Institut Pasteur, Paris, France) has given a seminar on April 19, 2011 entitled: "The mechanisms of prion intracellular replication and spreading: role of tunnelling nanotubes".
Date: Tuesday, 19 April 2011
Time: 9:00 a.m. - 11:00 a.m.
Venue: Seminar Room 7, LG/F, Laboratory Block, Faculty of Medicine Bldg, 21 Sassoon Road, Pokfulam, Hong Kong
Abstract:
Transmissible spongiform encephalopathies (TSE) result from a post-translational alteration in the conformation of a host-encoded GPI-anchored protein called PrPC. Conversion of the normal protein to the scrapie isoform PrPSc is the key event in the pathogenesis of these diseases. In familial forms, the conversion may occur spontaneously as a result of mutations in the PrP gene. Defining the mechanisms of PrPSc generation and the cellular basis for the pathogenic conversion of PrP is necessary to understand the pathogenesis of TSE. The intracellular compartment where PrPC - PrPSc conversion occurs and how this process leads to neurological dysfunction are still unknown. We have analysed the biosynthethic/degradative pathway, exocytic/endocytic trafficking, and the membrane compartmentalization of PrPC and of some mutants responsible for the hereditary diseases. In infected cellular models we are studing the site of pathological conversion and the intercellular spreading. We have recently shown that prion conversion occurs in the recycling compartment (Marijanovic et al., 2009), thus opening the door to novel therapeutical approaches.
Another unresolved question is how prions spread from the periphery of the body (normally the intestine as common site of prion access) to the central nervous system (CNS) and sequentially spread inside the CNS. We were able to show formation of Tunneling nanotubes (TNTs) containing PrPC and PrPSc between cells of the same and different origins including catecholaminergic neuronal cell line (CAD) as well as between dendritic cells (DC) and primary neurons (Gousset et al., 2009). TNTs are thin actin containing membrane tubular connections, detached from the substrate, that form bridges between cells, and may therefore represent an efficient mechanism for the transfer of PrPSc, by the cells at the peripheral entry-site to neurons in vivo. Indeed we demonstrated that TNTs are responsible for the spreading of infectious prions between different cells in colture (Gousset et al., 2009). We have futher shown that immune DCs uptake prions and spread them to neurons via TNTs (Langevin et al., 2010). Based on these data we propose that through the establishment of TNTs, peripheral dendridic cells can spread infection to neurons of the PNS and then by retrograde transport to the CNS. This discovery could have major impacts on prion research and in other fields of cell biology and medicine.
Croucher-Pasteur Exchange Programme: In collaboration with the International Affairs Department of Institut Pasteur and the Croucher Foundation, the Centre is establishing an exchange programme for students and post-doctoral fellows resident in Hong Kong in order to strengthen the scientific collaboration between Hong Kong and France. A 2 to 3 year scholarship covering travel, living and university registration expenses will be available for students and post-doctoral fellows resident in Hong Kong wishing to perform research work in laboratories of Institut Pasteur Paris. A lecture series of Pasteur scientists is organised to enable Hong Kong students to meet personally principal investigators from Institut Pasteur, know their scientific work and prospects of pursuing scientific work in their laboratories.