Disruption of morphogenic and growth pathways in lysosomal storage diseases

Abstract

The lysosome achieved a new protagonism that highlights its multiple cellular functions, such as in the catabolism of complex substrates, nutrient sensing, and signaling pathways implicated in cell metabolism and growth. Lysosomal storage diseases (LSDs) cause lysosomal accumulation of substrates and deficiency in trafficking of macromolecules. The substrate accumulation can impact one or several pathways which contribute to cell damage. Autophagy impairment and immune response are widely studied, but less attention is paid to morphogenic and growth pathways and its impact on the pathophysiology of LSDs. Hedgehog pathway is affected with abnormal expression and changes in distribution of protein levels, and a reduced number and length of primary cilia. Moreover, growth pathways are identified with delay in reactivation of mTOR that deregulate termination of autophagy and reformation of lysosomes. Insulin resistance caused by changes in lipids rafts has been described in different LSDs. While the genetic and biochemical bases of deficient proteins in LSDs are well understood, the secondary molecular mechanisms that disrupt wider biological processes associated with LSDs are only now becoming clearer. Therefore, we explored how specific signaling pathways can be related to specific LSDs, showing that a system medicine approach could be a valuable tool for the better understanding of LSD pathogenesis.