Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the selective death of both upper motor neurons in the motor cortex, and lower motor neurons in the brainstem and spinal cord (Azuma et al., 2018). Loss of these neurons causes generalized muscle weakness, spasticity and muscle atrophy, leading to progressive paralysis until death caused by respiratory failure (Cozzolino et al., 2012; Taylor et al., 2016). About 90% of ALS cases are considered sporadic (sSLA), while the remaining 10% are familial (fSLA), although they present the same clinical phenotypes and neuropathological features. ALS is a multifactorial disease, determined by the alteration of several key processes for cell viability. Although the contribution of each of them to ALS pathogenesis has not been fully clarified, the regulation of the integrated stress response (ISR), the nucleo-cytosolic transport of RNAs and proteins, as well as the regulation of alternative splicing seem to play a particularly relevant role. Recently, it has been shown that the activation of the ISR induces the accumulation into stress granules (SGs) of important factors that are mediators of the molecular traffic between the nucleus and the cytosol, such as importin-?1, importin- ?2 and exportin-1 (Zhang et al., 2018). This suggests the existence of a functional connection between the activation of the integrated stress response and the regulation of nucleo-cytosolic trafficking of RNAs and proteins. Recently, we have observed in our lab that pharmacological activation of ISR in HeLa cells by sodium arsenite (NaAs) or thapsigargin (TG) treatment induces a strong decrease in the nuclear distribution of Cajal Bodies (CBs) and Gems. These are membrane-less organelles that assist the maturation and storage of UsnRNPs (U-rich small nuclear ribonucleoproteins), the key constituents of the spliceosome machinery, and SMN complex, essential in the cytosolic assembly of UsnRNPs. Overall, these data indicate that the altered localization and the reduced availability of nucleo-cytosolic mediators may disturb the transport of UsnRNPs between the nucleus and the cytosol, and that the modulation of this process may represent a mechanism of regulation of gene expression under stress conditions. However, the mechanisms regulating this process have not been investigated so far, nor it is clear whether dys-regulation of such process might be involved in ALS pathogenesis. On this basis, the first aim of this study was to define the mechanism by which the pharmacological activation of the ISR regulates the dynamics of Cajal Bodies, and to verify whether this has an effect on the regulation of alternative splicing. Further, the second aim of this study was to investigate whether the activation of the ISR induced by the expression of ALS proteins is functionally related to the observed reduction of nuclear CBs, and to verify whether the previously defined mechanism of regulation of UsnRNPs trafficking via the importin-?1/SPN1 import machinery in response to stress is impaired in ALS conditions. Results from our study indicate that: i. the activation of the ISR in response to stress induces changes in the regulation of alternative splicing by modulating the nucleo-cytosolic trafficking of UsnRNPs that is mediated by the snurportin1/importin-?1 machinery; ii. in cells expressing mutated proteins associated with ALS, this regulatory mechanism is impaired and mutant ALS proteins directly affect the nucleo-cytoplasmic transport of UsnRNPs, independently from or downstream ISR activation.