Science, Technology and Engineering

Orian Laboratory

Department of Biochemistry

Research - Multiple Sclerosis

Multiple Sclerosis (MS) remains a poorly understood disorder. The primary cause of the disease is unknown and its course remains unpredictable. In its most common form, known as relapsing-remitting MS (RR-MS), the disease is characterized by exacerbations followed by remissions with partial or full recovery. Eventually, however, most patients enter a stage of continuous deterioration, known as secondary progressive MS (SP-MS). Another form that is seen less commonly is PP-MS, where there is relentless progression without remissions.

Recent years have seen a shift in the understanding of MS pathology. While traditionally considered to be a primary demyelinating condition with sparing of axons, data from human biopsy, post-mortem studies, MRI studies, and animal models, have clearly demonstrated frank axonal injury associated with pathological change in adjacent ‘normal-appearing-white-matter’ (NAWM) at early stage. These observations have given rise to the ‘axonal hypothesis’, which states that cumulative axonal injury underlies disease progression. Subsequently, efforts to identify mechanisms of damage and develop effective neuroprotective therapies have been refocused.

Concurrent with these studies, evidence of axon-glia and glia-glia networks and communication have been appearing. These data emphasize the existence and importance of cross-talk and interdependence between the cellular CNS elements, namely astrocytes, microglia, oligodendroglia and nerve cell bodies and axons. A picture of an immensely complex inter-related and constantly communicating multi-dimensional network emerges in which change or damage to one element will inevitably be transmitted throughout the whole system. It is in this context that we began studies of the interrelationships between inflammation, demyelination, axonal damage and glial responses in the pre-clinical and onset stages of murine models of RR-MS and PP-MS. These studies clearly demonstrate the occurrence of widespread axonal damage and significant astrocyte hypertrophy before large-scale parenchymal invasion of inflammatory cells, particularly T cells, before widespread demyelination and before microglia activation. We subsequently formulated the hypothesis that glial cells have a significant role in the development of axonal damage at the earliest stage in MS.

Current projects include:
1. Further investigations of the relationship between astrocyte responses and other pathological processes (inflammation, axonal damage, demyelination), by combining standard histological techniques, immunochemistry, confocal microscopy and electron microscopy.
2. In vitro approaches to assess whether astrocytic responses are likely to be a cause or effect of axonal degeneration.
3. The use of defined mutants to map glial responses and their effects.