To attempt to obtain crystals of the lipophilic proteins and of the peripheral basic protein of myelin.
To determine the molecular structure of these important constituants of the central nervous system in its myelin sheath membranes.
This should be a first step towards the understanding of the molecular basis of neurodegenerative diseases such as multiple sclerosis.
The proteins of myelin, the protective sheath enveloping neurones, are highly lipophilic membrane bound proteins (PLP), or associated with the membrane surface (MBP). While their primary structures (their amino-acid sequences) are known, in particular through work of some of the teams involved in the present project, their detailed 3D-structure, as it occurs in the membrane, is not precisely determined. It is therefore impossible so far to understand at the molecular level the exact mechanism of mutations leading to the widespread neurodegenerative diseases generally linked with myelin dysfunction, and therefore to design drug therapy on a rational basis.
The programme comprises the isolation of pure myelin proteolipids, either by the use of powerful analytical procedures established by team 1 for the PLP/DM-20 family and by team 3 for MBP, or through the recombinant technologies introduced by team 6. The pure proteolipids will then be incorporated in a variety of phospholipids, especially synthesised by team 5 for the purpose, with short or longer side-chains, and various headgroups. The techniques developed by team 7 with other lipophilic membrane proteins to obtain cubic phase organisations will be used to attempt to induce formation of single crystals suitable for X-ray analysis by team 2. These lipid/protein systems will also be studied with the membrane probes developed by team 1 to define their topography within the membrane. Physical studies such as ATR-FTIR spectroscopy in the hands of team 4, should furthermore help in defining the secondary structures of these proteins within the membranes.
The study of pathological variants will be performed by a joint effort of most or all teams involved, in the hope to learn enough on the molecular basis of neurodegenerative diseases to lead eventually to intelligent drug design.
Funding SchemeCSC - Cost-sharing contracts