A key challenge in the study of amyotrophic lateral sclerosis (ALS) is that the affected cells, mainly motor neurons (MNs) and muscle cells (MCs), are difficult to isolate and work with in vitro. In this study, we aimed to investigate the pathological features of ALS using cultured dermal fibroblasts, whose isolation requires a minimally invasive biopsy. [SG1] Morphological and biochemical analyses revealed pronounced cytoplasmic buildup and aggregation of TAR DNA-binding protein 43 (TDP-43) in fibroblasts from ALS patients, reflecting alterations commonly observed in MNs. Moreover, transferring culture medium from patient-derived fibroblasts to control donor-derived cells resulted in the latter developing similar TDP-43 cytoplasmic aggregations, indicating a prion-like mechanism in the transmission of TDP-43 pathology within this model. Given prior reports that protein-kinase inhibitors can restore TDP-43 nuclear localization and avoid cell-to-cell propagation in immortalized patient-derived lymphoblast, we tested these compounds in our model and found that they significantly restored the TDP-43 nuclear localization in patient-derived fibroblasts as well. However, recognizing the limitations of fibroblasts in capturing all pathophysiological mechanisms in MNs and MCs, we applied reprogramming techniques to convert the fibroblasts into disease-relevant cell lineages, such as induced myotubes (iMTs), and assessed the reliability of these approaches for our purposes. The iMTs derived from fibroblasts isolated from ALS patients exhibited cytoskeletal disruptions, including sarcomeric architecture damage, and reduced viability. Overall, our findings indicate that fibroblasts along with cells reprogrammed from them, such as iMTs, can serve as valuable models for understanding ALS pathogenesis, identifying therapeutic targets, and evaluating potential treatments.