Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons (MNs). Recently, mutations in the UBQLN2 gene, encoding ubiquilin 2, have been identified in hereditary forms of ALS and ALS with FrontoTemporal Dementia (ALS-FTD). These mutations induce the formation of ubiquilin-2-positive aggregates in the spinal cord of patients with ALS and in the brain of patients with ALS-FTD, as well as in other familial forms and in sporadic forms of ALS and ALS-FTD. The role of ubiquilin 2 seems to be crucial in the pathogenesis of the different types of ALS, due to its involvement in proteostasis. To understand the physiopathology of the disease and to envision therapeutic strategies, we have generated an ubiquilin 2-linked ALS and ALS-FTD mouse model which recapitulated disease associated phenotypes, after intracerebroventricular (ICV) injection of Adeno Associated Virus serotype rh10 (AAV10) vectors, containing the cDNA encoding mutated ubiquilin 2. Furthermore, mass spectrometry analysis revealed a loss of interaction between the mutant protein and one protein necessary for cytoskeleton maintenance of neurons, the α-spectrin. Finally, we have observed that Methylene Blue increased the number of inclusions in mice expressing the mutant ubiquilin 2. In conclusion, this study presents a solid paradigm to study the involvement of ubiquilin 2 in ALS and can be used for the development of effective therapeutic strategies.