Amyotrophic Lateral Sclerosis: New Insights into Underlying Molecular Mechanisms and Opportunities for Therapeutic Intervention

Recent years have witnessed a renewed interest in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a late-onset progressive degeneration of motor neurons. The discovery of new genes associated with the familial form of the disease, along with a deeper insight into pathways already described for this disease, has led scientists to reconsider previous postulates. While protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, and excitotoxicity have not been dismissed, they need to be re-examined as contributors to the onset or progression of ALS in the light of the current knowledge that the mutations of proteins involved in RNA processing, apparently unrelated to the previous “old partners,” are causative of the same phenotype. Thus, newly envisaged models and tools may offer unforeseen clues on the etiology of this disease and hopefully provide the key to treatment. Antioxid. Redox Signal. 17, 1277–1330. I. Introduction II. Genetics of ALS A. ALS loci 1. ALS1–SOD1 2. ALS2–Alsin 3. ALS4–SETX 4. ALS5–SPG11 5. ALS6–FUS 6. ALS8–VAPB 7. ALS9–ANG 8. ALS10–TDP43 9. ALS11–FIG4 10. ALS12–OPTN 11. Other genes B. Gene expression in ALS 1. Epigenetic regulation of mRNA transcription in ALS 2. Post-transcriptional regulation of mRNA expression in ALS 3. ALS transcriptome 4. ALS proteome and biomarkers III. ALS Is a Multifactorial Disease A. Protein aggregation and impairment of axonal transport B. Excitotoxicity C. Organelle dysfunction 1. Mitochondria a. SOD1 localization and import into mitochondria b. Mitochondria and oxidative stress c. Mitochondrial motility, dynamics, and turnover d. Mitochondrial apoptosis 2. Endoplasmic reticulum and Golgi apparatus a. Morphological alterations of the ER and Golgi apparatus b. ER stress and its sensors c. TDP-43 and VAPB in ER stress 3. Nucleus IV. RNA Dysmetabolism and ALS A. Structure and function of FUS and TDP-43 B. FUS/TLS and TDP-43 and the pathogenesis of ALS V. Non-Cell-Autonomous Death of MNs A. Neurons and glia B. Contribution of other cell types C. Extracellular signals VI. Therapeutic Approaches A. Pharmacological therapies in ALS/clinical update B. New strategies 1. Growth factor therapies in ALS 2. Gene therapies in ALS 3. Stem cell therapies in ALS VII. Concluding Remarks