3. Mitochondria as therapeutic targets in ALS Finding a cure for ALS has thus far been unsuccessful. Targeting mitochondrial dysfunction presents an attractive treatment option due to the widespread prevalence of mitochondrial dysfunction in disease. Potential therapeutic strategies have aimed to decrease ROS generation, increase mitochondrial biogenesis, inhibit apop-
totic pathways or dampen excitotoxicity.The only FDA drug approved for use in ALS is Riluzole. However, Riluzole only extends survival by approximately 3months. The mechanism by which Riluzole acts to improve survival is unclear. Some evidence suggests that Riluzole decreases ROS through induction of glutathione synthesis [219]. However little effect was observed on basal levels of ROS, and therefore Riluzole may only act in this way in the context of elevated ROS levels. Riluzole has been found to display a range of effects on glutamatergic signalling at the synapse, leading ultimately to attenuation in calcium handling requirements. Indeed, treatment in vitro with Riluzole prevents motor and cortical neuron loss induced by sustained glutamate increase and elevated ROS levels [220]. Furthermore, Riluzole has been demonstrated to reduce inward calcium currents and rescue the axonal transport of neurofilaments [221,222]. Attenuation of inward calcium currents is predicted to alleviate stresses on cytosolic and mitochondrial calcium buffering mechanisms and potentially decrease cytosolic calcium levels with knock-on effects on ROS generation and mitochondrial function. However, with the limited effect on prognosis offered by Riluzole, alternative therapies are required for the treatment of ALS. Despite many drug-based and gene therapy approaches target-
ing mitochondrial dysfunction in ALS, neither treatments aimed at increasing mitochondrial function and survival nor those aimed at reducing oxidative stress have yielded significant results in clinical trials, despite promising trials in animal models [223]. For example, several drugs targeting mitochondrial function and/or ROS such as Coenzyme Q10, Dexpramipexole, Olesoxime and Creatine all showed initial success in animal models but were unsuccessful in human clinical trials [224–231]. Reducing ROS using Edaravone, a free radical scavenger was successful in mouse models but had only a small effect on human disease progression [232,233]. Similarly, minocyline, an anti-apoptotic and anti-inflammatory drug which extended survival in mouse models, failed in a human phase III randomised trial [234]. The discrepancy between the results from mouse models and human trials highlights the disparity between models and the human disease, and the need for better disease models [235]. In addition, the wide range of mitochondrial dysfunction in ALS means that a single therapy is unlikely to attenuate all aspects of dysfunction. Therefore, identifying which of the mitochondrial dysfunctions are relevant to disease causation and progression will continue to be important for the development of neuroprotective therapies in ALS. Targeting specific proteins dysregulated in ALS may provide alternative therapy avenues. Indeed a blocking peptide that prevents the abnormal interaction between mutant SOD1 and Bcl-2 has been shown to prevent apoptosis and
improve mitochondrial function in SOD1 G93A transgenic mice. Dime por favor la ideas prinicpales