Charcot-Marie-Tooth type 2B (CMT2B) is a peripheral sensory neuropathy caused by mutations in the late endosome/lysosome associated small GTPase Rab7A. While progress has been made in characterizing the biochemical and functional consequences of CMT2B-causing mutations, the mechanisms leading to the degeneration of neurons with very long axons are still unclear. We recently found that Rab7-positive acidic compartments are involved in axonal protein synthesis, a process that is essential for neuronal function and maintenance. These intriguing findings prompted us to better understand lysosomal function in subcellular protein synthesis and how it is affected in CMT2B neurons. We first generated a new CMT2B knock-in mouse model carrying Rab7aN161T mutation using CRISPR/Cas9 technology. Detailed characterization of the lysosomal pathway in cortical and DRG CMT2B neurons revealed changes in lysosomal morphology and trafficking. Next, we demonstrated that protein synthesis is altered in CMT2B neurons, including distal compartments, by puromycin labeling and click chemistry assays. We then identified the transcriptome associated with lysosomes in neuronal cells (N2a) and found the presence of nuclear-encoded mitochondrial mRNAs. Moreover, our preliminary evidence suggests defects in mitochondrial morphology and function in CMT2B neurons. Overall, our results support a direct role for lysosomes in controlling subcellular protein synthesis in neurons and impairments of this process could contribute to CMT2B pathogenesis.