Hereditary Spastic Paraplegia 4 (HSP-SPG4) is a rare neurodegenerative disease characterized by degeneration of the corticospinal tract caused by mutations of the SPAST gene encoding Spastin, a microtubule-severing protein. We recently showed that gain-of-function cytotoxicity of the M1 isoform of Spastin is sufficient to account for the disease. As a result of the toxic properties of mutant-M1, microtubules in the corticospinal tracts become less acetylated, while the activity of Histone Deacetylates 6 (HDAC6) is correspondingly increased. In addition, it has been reported that Tau, a regulator of microtubule stability and axonal transport, can be deacetylated by HDAC6 in Tauopathy which could be reversed by inhibiting HDAC6 activity. Inhibition of HDAC6 activity has also been shown to repair axonal degeneration and demyelination. Based on the abnormal HDAC6 activity, we aimed to investigate the role of Tau in HSP-SPG4 pathology and the potential effects of mutant Spastin on demyelination. Using the spinal cord and motor cortex from the SPG4-mouse, total Tau protein levels were analyzed by western blot. In addition, the effects of mutant Spastin on demyelination were analyzed by immunofluorescence of the Myelin-Basic-Protein and βIII-Tubulin in glial-neuronal cortical co-cultures. We showed that the protein levels of 70 and 50 kDa Tau were increased in the SPG4-mouse model, and Spastin could play a role in demyelination. Taken together, our findings revealed a relationship between the gain-of-function toxic effects of mutant Spastin with Tau pathology and demyelination, and these results provide a new perspective on understanding the pathophysiology of HSP-SPG4.