ALS is a neurodegenerative disorder that causes the gradual deterioration of motor neurons (MNs) resulting inevitably in their eventual loss. The onset of the disease is triggered by an early pathological event that is uncertain in nature and spreads topographically from a specific point. This ultimately leads to the manifestation of symptoms throughout the neuromuscular system that culminate in paralysis and death. Therefore, we suggest that investigating the early neurodegenerative events in MNs should start with modelling the pathological phenomenon of disease spreading. Our approach involves investigating the secretomes of various cell types affected by TDP-43 pathology, including neurons, muscle, and glia. We anticipate that these secretomes will trigger significant changes in the gene expression and function of healthy human MNs. Our preliminary research has demonstrated that chronic exposure to the secretome of patient-derived myotubes results in hyperexcitability, followed by hypoexcitability and neuronal dysfunction, which are common features for other neurodegenerative diseases. Furthermore, RNA-seq analyses of neurons exposed to the ALS secretome have revealed changes in their transcriptomic profile, including upregulation of cell-cycle and DNA metabolism pathways, indicating a transcriptome resembling an immature state. Consistent trends have been observed in various RNAseq datasets from ALS neurons, including those obtained from iPS cells, mouse models, and spinal cord tissue. Based on our initial findings, we suggest that hyperexcitability induced by the ALS-secretome may lead to the immaturity of MNs, potentially playing a crucial role in the early mechanisms of neurotoxicity caused by the intercellular propagation of TDP-43 pathology.