Multiple Sclerosis is characterised by the presence of inflammation, demyelination and axonal loss at multiple sites throughout the central nervous system. All these pathologies contribute to a loss of neurological function and the resulting symptoms are predominantly related to the site of the damage. Whereas focal areas of inflammation and demyelination are thought to be responsible for the acute symptoms that occur during relapses, the chronic progressive loss of neurological function is thought to be due to a combination of a failure of remyelination, axon loss and neurodegeneration.
The Multiple Sclerosis research group at Imperial College is studying the cellular and molecular events that lead to these pathological changes, in particular the failure of remyelination and the progressive neurodegeneration, using a combination of human post-mortem tissues, experimental models and cell culture systems.
Mechanisms of demyelination and neuronal loss in multiple sclerosis
Axonal damage and neuronal loss is now thought to be an early feature of MS pathology (Anderson et al, 2009; Kim et al, 2010) and evidence suggests that its accumulation may be the pathological correlate for the progression of disability. Recent evidence suggests a major role for neuronal loss in the cortical grey matter in MS (Magliozzi et al, 2007; Papadopoulos et al, 2009; Magliozzi et al, 2010). Therefore, we are using human tissues and experimental models of MS to investigate the mechanisms responsible for this neuronal loss. In collaboration with the group of Francesca Aloisi in Rome, we have demonstrated the involvement of ectopic meningeal lymphoid structures in cortical pathology in MS, in particular in sub-pial demyelination and neurodegeneration. The presence of these structures and associated pathology is associated with a more rapid and aggressive disease course (Magliozzi et al, 2007; Magliozzi et al, 2010; Howell et al, 2011; Choi et al, 2012). Our current studies are investigating the molecular nature of the mediators responsible for this pathology (Gardner et al, 2013).
Remyelination in MS
Myelin repair in the adult CNS is thought to be brought about via the generation of new oligodendrocytes from quiescent progenitors, but very little is known about the signals that cause them to become reactivated in order to differentiate into oligodendrocytes for remyelination and to support their survival. We are investigating the characteristics of these cells in vitro using a combination of cellular and molecular techniques and are particularly interested in contact dependent signals from the axon that stimulate survival and process outgrowth. Recent studies in this laboratory (Palser et al, 2009) have demonstrated a role for the neural cell adhesion molecule (NCAM) in this process.
Remyelination in the MS brain is suggested to fail at an early stage, although very little is known about the natural history of this repair process in the human brain. Our recent studies have indicated that remyelination can be extensive in MS despite a long disease course (Patani et al, 2007).
The Multiple Sclerosis Society Tissue Bank
The Tissue Bank was set up at the beginning of 1998, funded by a 5-year grant from the UK MS Society, to provide a reliable source of post-mortem MS CNS material for researchers around the UK. We have developed extensive protocols for collection, dissection and storage of brain, spinal cord and CSF, to ensure that the tissue is of maximum use for a wide variety of experimental techniques (Durrenberger et al, 2010; 2012). This has proven to be extremely successful and we are now supplying tissue for research projects throughout the world. All tissue collected by the bank is obtained via a prospective donor scheme. In addition to research into optimizing the efficiency of our tissue banking, we are carrying out a number of studies looking at the best ways to characterise the variety of pathologies within MS tissue using combinations of histology, immunohistochemistry and molecular studies. The MS Tissue Bank is currently funded by a programme grant from the UK MS Society until 2014 and operates alongside the Parkinson’s Disease Society Tissue Bank.