Pathological characterisation of dysferlin expression in Multiple Sclerosis (MS) and its relationship to clinical outcomes.

Progressive MS (PMS) is characterised by age-related neurodegeneration that often manifests as irreversible motor disability. A recent genome wide association study implicated dysferlin as a potential locus associated with motor disability severity in PMS. Aberrant dysferlin expression in Alzheimer’s disease suggests a role in age-related neurodegeneration. We sought to evaluate dysferlin expression and its relationship to neuropathological and clinical outcomes in a large post-mortem PMS cohort.

Dysferlin was expressed in long-projection neurons (layers 3b and 5 of the motor cortex, ventral horn, and Clarke’s column). Large diameter spinal cord axons preferentially expressed dysferlin where membrane-associated staining was observed. Monocytes and occasional endothelial cells also showed dysferlin immunolabelling. In controls, motor cortical neuronal and spinal cord axonal dysferlin expression strictly associated with age. In MS, multivariate models showed age and disease severity jointly influenced cortical dysferlin expression, particularly in layer 5 motor cortical neurons where higher densities associated with older age and shorter time to wheelchair use. In the spinal cord, axonal dysferlin expression also correlated with disease severity, particularly in the long tracts where increased expression correlated with shorter time to wheelchair use.