Mechanisms of axonal loss in MS

Valeria Ramaglia, PhD

Axonal loss is a key feature of MS pathology and determines disability in secondary progressive patients. The cause of axonal loss in MS is unknown. Previous research showed that axons are extremely susceptible to attack by the complement (C) system. Complement is a major component of innate immunity. Activated complement fragments recognise and eliminate danger signals whereas regulators protect healthy tissue from complement attack. If the balance between activation and regulation is disrupted, complement can damage healthy tissue. This process can involve a strong inflammatory response (such as during processing of bacteria) or it can be very subtle (such as during clearance of apoptotic cells or elimination of supernumerary synapses during development).

Figure: C3 (red) deposition on axons in MS that colocalizes with HLA (green)-positive microglia cells in normal appearing white matter of MS

Activated complement fragments have been previously detected in MS lesions on myelin segments or myelin debris mostly within active, foamy macrophages. Therefore, the role of complement in MS has been associated with demyelination and a strong inflammatory response. Whether complement plays a role in axonal loss in MS is unknown.

We hypothesize that complement contributes to axonal loss in MS by attacking axons left vulnerable by demyelination and/or by directly targeting neurons and synapses, contributing to disease progression. We combine molecular and neuropathological analysis of post-mortem human brain with functional studies in animal models of MS. The aim is to elucidate the mechanisms leading to neuropathology, identify targets for therapy and test novel treatments to prevent, halt or repair axonal damage.