Group leader: 

Anna Williams

Position: 

Wellcome Trust Intermediate Fellow and Honorary Consultant Neurologist

Contact: 

anna [dot] williams [at] ed [dot] ac [dot] uk

Aims
We want to 1) understand why remyelination fails in Multiple Sclerosis and 2) improve the efficiency of remyelination in Multiple Sclerosis.

Background
In the brain and spinal cord, nerves are covered by an insulating sheath of membrane called a myelin sheath. This allows fast transmission of electrical impulses and protects and maintains the nerve. In Multiple Sclerosis (MS), patches of demyelination occur, where these myelin sheaths are damaged and stripped off the nerve. This causes neurological symptoms such as paralysis, sensory changes and blindness. Replacement of these myelin sheaths (remyelination) can happen in MS, which can restore nerve function. This is generally inefficient, and often a scar forms instead, causing a long-term problem for the patient. Remyelination is carried out by oligodendrocyte precursor cells which are attracted to the damaged area, make contact with nerves, mature and form myelin sheaths to replace those that are damaged. A failure of remyelination can occur with a problem at any one of these steps. If we can understand the mechanisms of each step, we may be able to manipulate them to improve the efficiency of remyelination.

Approach and progress
We are particularly interested in the molecules controlling the migration and maturation of oligodendrocyte precursor cells in the adult central nervous system. The migration of these repairing cells into MS lesions and their maturation to form myelin sheaths are critical in remyelination. In particular, we are investigating the guidance molecules Semaphorin 3A and 3F and their receptors. These are repulsive (semaphorin 3A) or attractive (semaphorin 3F) signals for oligodendrocyte precursor cells.
We use in vitro, ex vivo and in vivo systems to tackle these questions. We manipulate levels of molecules of interest with recombinant proteins, lentiviral transduction and using transgenic animals.
We are currently developing an ex vivo model of remyelination which is semi-automated in order to have a moderately high throughput screen to quickly test potential molecules affecting remyelination.

MS plaques containing much Sema3F attract oligodendrocyte precursor cells and go on to remyelinate. MS plaques containing much Sema3A repel oligodendrocyte precursor cells and stay chronically demyelinated.

Demyelinated lesion in the corpus collosum (delineated with black line). Myelin is stained blue with Luxol fast blue/cresyl violet stain.

Myelination is assessed by immunofluorescence for Myelin Basic Protein (MBP green), in comparison to axonal staining (Neurofilament (NF) red). Scale bars 10 µm.
A. Initial myelination is robust.
B. A day after LPC treatment, virtually no myelin sheaths remain, but Olig2-positive immature oligodendroglial cells (blue) survive.
C. Remyelination occurs, with reformation of paranodes (stained with caspr) and shorter internodes.

Clinical work
I am also an honorary consultant neurologist, and I carry out general neurology and MS clinics in the Royal Infirmary of Edinburgh and in Queen Margaret Hospital, Dunfermline. I am involved in the CUPID trial for MS.

Selected publications

• Piaton G, Williams A, Seilhean D, Lubetzki C. Remyelination in Multiple Sclerosis. 2009. Prog. Brain Res 175:453-464.
• Williams A, Piaton G, Belhadi A, Théadin M, Aigrot M-S, Petermann F, Thomas J-L, Zalc B, Lubetzki C. 2007. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain 130:2554-2565.
• Williams A, Piaton G, Lubetzki C. 2007. Astrocytes - friends or foes in Multiple Sclerosis? Glia 55(13):1300-1312.
• Lubetzki C, Williams A, Stankoff B. 2005. Promoting repair in multiple sclerosis: problems and prospects. Curr Opin Neurol 18(3):237-244.

Funding
Wellcome Trust