Impaired lysosomal proteolysis in developing neurons induces protein aggregation and disrupts morphogenesis and neuromaturation

This is the authors' abstract. We don't add key points for this paper.

Lysosomes play a central role in the degradation of intracellular substances. Through this degradative capacity, lysosomes contribute to biological homeostasis and are particularly critical for the maintenance and function of neurons. Deficiencies in various lysosomal proteins cause a group of conditions known as lysosomal storage disorders, which often present with developmental delay and other neurological symptoms. In addition, defects in lysosomal function and the autophagic pathways that deliver intracellular substrates to lysosomes have been linked to neurodevelopmental disorders. However, the contribution of lysosomal degradative capacity to neurodevelopment has not been well appreciated. In this study, we aimed to examine the relationship between overall lysosomal proteolytic capacity and neuronal development using primary cultured neurons at early developmental stages. We found that lysosomal protein expression and proteolytic activity increased with neuronal maturation, suggesting that lysosomal proteolysis may play an important role in neuronal development. Treatment of cultured neurons with specific inhibitors of lysosomal proteases during development impaired morphogenesis, as indicated by a significant decrease in neurite length and complexity, along with decreased expression of neuronal lineage marker proteins. Furthermore, we observed that neurons with development impaired by lysosomal protease inhibition accumulated aggregated proteins-some of which were ubiquitinated-in the cytoplasm. These aggregates were enriched with various proteins related to neurodevelopment. These findings provide new insights into the previously underappreciated role of lysosomes in neuronal development.