Fig. 2

Overview of ALS pathology with a focus on axons. As axons are damaged from the initial stage of ALS, the dying-backward hypothesis, in which motor neurons are damaged from the distal part, has been proposed. RNA-seq of axon fraction shows the presence of intra-axonal transcription factors (e.g., AP-1), although the pathological significance remains unknown. NMJs are the key link between motor neurons and skeletal muscle, and NMJ disconnection is commonly observed in several types of ALS. The local translation is a molecular mechanism necessary for axonal homeostasis. In contrast, when the proteasome and autophagy are dysregulated, abnormal protein aggregation is triggered. Mitophagy is a form of autophagy, and mitochondrial pathology is a common feature of various neurodegenerative diseases. Furthermore, impaired axonal transport impairs the transport of RNA/Protein complex, lysosomes, and mitochondria. Many ALS-causing genes contribute to cytoskeleton function. Morphologically abnormal axon branching has been observed. The pathophysiology of the cell body, which is closely related to the axonal pathology, is also important. Cryptic exon induced nonsense-mediated decay (NMD) or aberrant proteins, persistent stress granules (SGs) formation, and nucleocytoplasmic transport defect have attracted attention as new therapeutic targets