p38 is activated in ALS [126,127], and p38 has been linked with kinesin hyperphosphorylation leading to inhibition Kinase Inhibitor Library clinical trial of kinesin-dependent mitochondrial transport [41]. Further, glutamate levels are increased in mSOD1 [128,129] and this can lead to activation of p38 [130]. Glutamate may also regulate axonal transport of mitochondria via increased calcium levels, which are known to lead to inhibition of anterograde and retrograde mitochondrial

axonal transport [131,132] via interactions with the mitochondrial protein Miro [43]. However, this cannot explain the anterograde-specific mitochondrial defects observed in primary motor neurone cultures from G93A mice [115]. Aggregation of mSOD1 could affect mitochondrial axonal transport by forming blockages in the axon. mSOD1 is known to aggregate by a process involving misfolding to form high molecular weight complexes [133–135]. mSOD1 also causes aggregation of neurofilaments and peripherin in HCIs or axonal spheroids, and ubiquitinated inclusions are present in most FALS cases. All of these abnormal pathologies could potentially block mitochondrial axonal transport. However they would be expected to block both anterograde and

retrograde transport. In motor neurones cultured from G93A mSOD1 mice [115], the defects in mitochondrial axonal transport are specific to the anterograde direction and lead to a reduction in the number of axonal mitochondria. The wealth of evidence implicating mitochondrial dysfunction as causal in the pathology of ALS has led to the Sorafenib chemical structure development of several mitochondrial targeted therapies. These include oral supplementation of creatine, a component of the cellular energy buffering system, and minocycline, an anti-inflammatory and inhibitor of caspase activity [136,137]. The neuroprotective effects of these compounds were identified in successful studies in transgenic mice [137–139]. However, this in vivo triumph has failed to translate into successful clinical therapy [140]. The failure of these therapies may be due to the fact that ALS is a multifactorial disease, and thus, targeting

specific mechanisms could be too focal to successfully impact on the overall progression of disease. Indeed, cumulative neuroprotective effects were noted when creatine, alongside minocycline, was administered in transgenic mouse models, Tryptophan synthase highlighting the potential for drug cocktails in the treatment of the disease [44,141]. In light of this, a mitochondrial-targeted novel compound, TRO19622 (olesoxime), has been developed, which has been shown to have protective effects in vitro and in vivo, promoting motor neurone survival in the former and promoting nerve regeneration following crushing in the case of the latter [142]. Additionally, administration of the drug to mSOD1 G93A mice saw an improvement in motor performance alongside a delay in clinical disease onset and extension of lifespan [142].