Inflammation and oxidative stress are thought to play determinant roles in the pathogenesis of amyotrophic lateral sclerosis (ALS). Degenerating motor neurons produce signals that activate microglia to release reactive oxygen species (ROS) and proinflammatory cytokines, resulting in a vicious cycle of neurodegeneration. The ALS-causing mutant protein Cu⁺/Zn⁺ superoxide dismutase SOD1-G93A directly enhances the activity of the main ROS-producing enzyme in microglia, NADPH oxidase 2 (NOX2), a well-known player in the pathogenesis of ALS. Considering that extracellular ATP through P2X₇ receptor constitutes a neuron-to-microglia alarm signal implicated in ALS pathology, we used primary microglial cells derived from transgenic SOD1-G93A mice and SOD1-G93A mice lacking the P2X₇ receptor to investigate the effects of both pharmacological induction and genetic ablation of receptor activity on the NOX2 pathway. We observed that, in SOD1-G93A microglia, the stimulation of P2X₇ receptor by 2′-3′-O-(benzoyl-benzoyl) ATP enhanced NOX2 activity in terms of translocation of p67^phox to the membrane and ROS production; this effect was totally dependent on Rac1. We also found that, following P2X₇ receptor stimulation, the phosphorylation of ERK1/2 was augmented in ALS microglia, and there was a mutual dependency between the NOX2 and ERK1/2 pathways. All of these microglia-mediated damaging mechanisms were prevented by knocking out P2X₇ receptor and by the use of specific antagonists. These findings suggest a noxious mechanism by which P2X₇ receptor leads to enhanced oxidative stress in ALS microglia and identify the P2X₇ receptor as a promising target for the development of therapeutic strategies to slow down the progression of ALS.

A common feature of non‐coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA‐binding proteins, thus affecting various steps of post‐transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)₃₁ repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)₃₁ repeats widely affected the distribution of Pur‐alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra‐cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.

Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1^G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1^G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1^G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.

Introduction: Wnt/β-catenin signaling is an evolutionarily conserved pathway having a crucial role in embryonic and adult life. Specifically, the Wnt/β-catenin axis is pivotal to the development and homeostasis of the nervous system, and its dysregulation has been associated with various neurological disorders, including neurodegenerative diseases. Therefore, this signaling pathway has been proposed as a potential therapeutic target against neurodegeneration. Areas covered: This review focuses on the role of Wnt/β-catenin pathway in the pathogenesis of neurodegenerative diseases, including Parkinson’s, Alzheimer’s Diseases and Amyotrophic Lateral Sclerosis. The evidence showing that defects in the signaling might be involved in the development of these diseases, and the pharmacological approaches tested so far, are discussed. The possibilities that this pathway offers in terms of new therapeutic opportunities are also considered. Expert opinion: The increasing interest paid to the role of Wnt/β-catenin pathway in the onset of neurodegenerative diseases demonstrates how targeting this signaling for therapeutic purposes could be a great opportunity for both neuroprotection and neurorepair. Without overlooking some licit concerns about drug safety and delivery to the brain, there is growing and more convincing evidence that restoring this signaling in neurodegenerative diseases may strongly increase the chance to develop disease-modifying treatments for these brain pathologies.