A study was recently reported in the press as showing promise for a cure for ALS. Although the content reported by the press is accurate, the interpretation by members of the ALS community is wrong: There is no way (yet) to cure ALS, but on the other hand the study reinforces and clarifies the long-suspected link between ALS and metabolism.
About 10 to 20% of cases of amyotrophic lateral sclerosis are familial, with the C9orf72 mutation being the most common cause of familial ALS. The pathological mechanisms of the C9orf72 mutation in ALS remain unclear. Indeed, the loss of function induced by a mutation of C9orf72 alone does not contribute to the deficits of lysosomal rapid axonal transport in C9orf72 motor neurons derived from stem cells.
Enormous energy needs The processes involved in the functioning of motor neurons are all very energy consuming, which raises the question of whether alterations in energy metabolism contribute to defective axonal transport. Apart from alterations in the microtubule machinery observed in a rare mutation causing ALS: FUS, until the present study, however, it had not been shown that the metabolism of motor neurons from ALS patients differed from those of healthy motor neurons.
OXPHOS is the metabolic pathway of mitochondria For their energy supply, neurons, unlike astrocytes, are primarily dependent on mitochondrial oxidative phosphorylation. Oxidative phosphorylation (or OXPHOS) is the metabolic pathway in which cells use enzymes to catalyze the oxidation of nutrients, releasing the energy needed to form ATP. In almost all aerobic eukaryotes, oxidative phosphorylation takes place within the mitochondria. During oxidative phosphorylation, electrons are transferred from electron donors to electron acceptors, such as oxygen, via redox reactions. These redox reactions release energy which is used to form ATP. This is a very efficient route for generating energy, compared to other processes using fermentation such as anaerobic glycolysis.
The importance of energy from mitochondria in axonal transport The extraordinary length of motor neuron axons - 20,000 times longer than the diameter of their soma - suggests a particular metabolic vulnerability of motor neurons to deficits in key processes involved in maintaining axon form and function.
The transport of mitochondrial cargo, unlike vesicular transport, depends on the availability of mitochondrial ATP. Defective transport of the cargo to the distal axon has been reported in several types of ALS, and not just in genes involved in the transport of proteins in the axon. It is well established from animal models of ALS that axon targeting results in delay in disease progression and improved survival and that prevention of motor neuron loss only, but not axonal degeneration, is insufficient to promote patient survival.
Demonstration of a modified axonal transport To better understand this question, the scientists studied induced pluripotent stem cell lines derived from autopsy of patients containing the most common mutation causing ALS, C9orf72. These stem cells have been matured into motor neurons. They then demonstrate that motor neurons affected by the C9orf72 mutation have (in vitro) shorter axons, an axonal transport of the mitochondrial cargo which is altered and a modified mitochondrial metabolism.
The scientists then show that this deregulation is selective for the spinal (motor) neurons of the anterior horn, and is absent in the spinal (sensory) neurons of the dorsal horn (deregulation in the spinal motor neurons of the ventral horn, but not in sensory neurons of the corresponding dorsal horn).
Gene therapy manipulating PGC1α restores a good phenotype of mutated motor neurons and their axons The scientists then carried out by gene therapy an alteration of the genome of the mitochondria in the motor neurons carrying the C9orf72 mutation which are derived from stem cells. This alteration of the genome corrected the metabolic deficit and also saved axonal length and transport phenotypes.
The scientists were able to stimulate mitochondrial function (and biogenesis) through the manipulation of its main regulator, PGC1α, leading to the rescue of axonal phenotypes, providing a new mechanical link between mitochondrial bioenergetics. and axonal dysfunction.
A link with TDP-43? These data suggest that targeting the PGC1α pathway may be highly relevant for neurodegeneration, as it is possible that there are other mechanisms leading to axonal dysfunctions observed in motor neurons with the C9orf72 mutation. For example, recent findings show that the repeated proteins of the C9orf72 dipeptide can lead to cytoplasmic aggregation of TDP-43. Thus, the pathology of TDP-43, observed in the vast majority of ALS cases, including C9orf72, modulates mitochondrial homeostasis by regulating the processing of mitochondrial transcriptions.
Conversely, TDP-43 exerts a toxicity by penetrating into the mitochondria and by specifically altering the OXPHOS I complex and by inhibiting its translation which causes mitochondrial dysfunction.
Finally, recent work from Onesto et al. showed that there is compensatory mitochondrial biogenesis, as evidenced by the upregulation of PGC1α, in dermal fibroblasts derived from patients with the C9orf72 mutation in ALS.
This suggests that despite the deleterious effects of the mutation, most cell types can compensate for mitochondrial dysfunction by stimulating biogenesis. The specific vulnerability to motor neurons could result in part from an inability of motorneurones to modulate this homeostatic mechanism when they face too much energy expenditure.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.