Multiple sclerosis (MS) is a disease characterized by inflammatory demyelination and a strong neurodegenerative component. Axonal damage is characteristically detected in MS brains, although the pathogenic mechanisms are not clearly understood. Here, we discuss the importance of HDAC1 localization as one of the potential mechanisms initiating damage in demyelinating conditions. We suggest the occurrence of a two-stage mechanism of damage. The first event is a calcium-dependent HDAC1 nuclear export in a CRM1-dependent manner and the second event is the interruption of mitochondrial transport resulting from the cytoplasmic localization of HDAC1. In the cytosol of neurons challenged by cytokines and excitatory aminoacids, HDAC1 formed complexes with motor-protein and microtubules and this resulted in blockade of axonal transport and release of cargo from motor proteins. We suggest that these findings might be the framework for future studies and for the development of novel therapeutic targets for axonal damage in demyelinating conditions.