Retromer as a critical regulator of endosome maturation?

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Retromer is an evolutioanry conserved multi-protein complex which recycles internalized integral membrane proteins from endosomes back to the plasma membrane or back to the trans golgi network. Mutations in retromer cause hereditary Parkinson's disease which makes a thorough mechanistic understanding of this complex necessary. We have recently identified a major new function for this complex in the control of the late endosomal/lysosomal small GTPases protein RAB7. In the absence of retromer or the retromer bound protein TBC1D5, RAB7 is no longer controlled in its activity state, which leads to gross hyperactivation and endo-lysosomal accumulation of this small GTPase. This hyperactivation causes defects in the RAB7 dependent autophagy of mitochondria. However, given the many functions of this small GTPase, the defects in mitophagy cannot be the only effect of deregulated RAB7. In this context, we have substantial preliminary data showing that the RAB7 mediated maturation of early into late endosomes is strikingly altered in the absence of retromer. This in turn leads to a range of observed trafficking defects, among them the aberrant sorting of lysosomal hydrolases, which are not delivered to lysosomes but instead secreted into the extracellular space. This proposal seeks to investigate the precise mechanistic basis of the observed defects to really begin to understand the novel function of retromer in the control of RAB7 activity. The knowledge gained here may well prove to be valuable for our understanding of retromer's role in Parkinson's disease.