Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disorder with rapid progression resulting in a fatal outcome on average only a few years after onset of first symptoms. Patients suffering from ALS present with muscle weakness, atrophy and spasticity due to loss of upper and lower motor neurons located in the motor cortex, brain stem and spinal cord. In approximately 20% of familial ALS the disease is caused by mutations in the Superoxide dismutase 1 (SOD1) gene. Mice overexpressing a mutant form of human SOD1 develop an ALS-like phenotype and are used most commonly to study the disease pathogenesis and the effect of therapeutic intervention.Considering the size of a motor neurons cell body its axon is incredibly long, extending into our extremities. For this reason, it is likely that a small defect of axonal transport affects the function and viability of the cell. Axonal transport is defined by the movement of motor proteins, i.e. dyneins and kinesins, that transport cargo by binding to and moving along microtubules. This process is regulated by a number of factors that are divided into two main groups: (a) microtubule-associated proteins (MAPs) that bind to and stabilize microtubules, of which tau is the most prominent one, and (b) post-translational modifications of tubulin that influence the recruitment of MAPs and motor proteins. Affecting one of these factors can disturb transport and induce cell death. Vice versa, cellular dysfunction can immediately affect axonal transport.Several observations link neurodegenerative diseases, including ALS, to defects of axonal transport and its regulation. In this study, we investigated the effect of two modifiers of transport, the tau protein and acetylation of α-tubulin, on the pathogenesis of ALS. First, we studied the significance of tau expression levels by studying the possible association of the H1/H2 polymorphism and ALS in different large and well-defined sporadic ALS patient populations, and by investigating the effect of the deletion of Mapt from the transgenic mouse model for ALS, the SOD1G93A mouse. We did not obtain experimental or genetic evidence for a role of tau protein levels in the pathogenesis of ALS. In this regard, ALS differs substantially from other neurodegenerative diseases, such as corticobasal degeneration, progressive supranuclear palsy and Alzheimers disease. In the second part, we studied the possible role of α-tubulin acetylation in motor neuron degeneration. This was done in vitro an in vivo by increasing or decreasing the expression of the putative α-tubulin acetylase ELP3 and the known α-tubulin deacetylases SIRT2 and HDAC6. Although we observed a neuroprotective effect of ELP3 in a zebrafish model with mutant SOD1-induced axonal outgrowth abnormalities, this effect is however unlikely to be dependent on α-tubulin acetylation. Deletion of mouse Sirt2 did not result in the expected increase in acetylated α-tubulin, nor did it influence the disease course in SOD1G93A mice. Finally, Hdac6 protein ablation positively affected the course of motor neuron degeneration in SOD1G93A mice and was associated with increased levels of acetylated α-tubulin. In conclusion, pharmacological inhibition of HDAC6 by a specific inhibitor like TubastatinA possibly provides a therapeutic strategy for the treatment of ALS and other neurodegenerative diseases.