Although inflammatory demyelination is considered to be the key feature in multiple sclerosis (MS) pathogenesis, histopathological investigations and MRI studies recently highlighted the extent of neuronal damage that occurs even in the early stages of the disease. We report the unusual case of a patient with Machado-Joseph disease (MJD; spinocerebellar ataxia (SCA) III) and discuss this coincidence in light current pathogenetic paradigms of CNS autoimmunity.