Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by the accumulation of aberrant proteins in motor neurons of the brain and spinal cord. Patients with ALS develop skeletal muscle weakness, resulting in death from respiratory paralysis, which usually occurs 2–4 years after clinical onset (Goutman et al., 2022). Although the precise pathological mechanisms remain elusive, several processes, including aberrant ribonucleic acid metabolism, altered proteostasis/autophagy, mitochondrial dysfunction, and compromised DNA repair, are reportedly involved in the onset and progression of ALS. Recently, increasing evidence suggests that disruption of cytoskeletal dysregulation could be attributed to ALS (Goutman et al., 2022). Profilin-1, an actin monomer-binding protein essential for the regulation of actin polymerization, has been identified as a causative gene of familial ALS. Profilin-1 mutations have been reported to result not only in a decreased F-actin arrangement (Fil et al., 2017) but also in altered stress granule dynamics and TAR DNA-binding protein of 43kD (TDP-43) aggregation (Fil et al., 2017). Transgenic mice with mutated profilin-1 not only recapitulate paralysis and motor neuron degeneration similar to ALS, but also show TDP-43 aggregation pathology, suggesting that actin dynamics are intrinsically involved in the pathogenesis of ALS. Cofilin, which is essential for actin depolymerization, has also been associated with the pathology of ALS. A previous report showed that cofilin is associated with the reduction of F-actin in induced pluripotent stem cell-derived motor neurons in patients with ALS with GGGGCC intronic repeat expansion in C9orf72, a common genetic form of familial ALS. Therefore, disruption of actin dynamics, including alterations in profilin-1 and cofilin, has been implicated in the pathogenesis of ALS, contributing to motor neuron degeneration and disease progression. In this perspective, we will focus on the role of actin dynamics as a neuronal barrier inhibiting aberrant protein deposition. Additionally, we will discuss on the potential of axon guidance molecules regulating actin dynamics as a novel therapeutic target.