We wondered whether retromer function could be enhanced if recruitment of the retromer CSC to membranes was stimulated. Rab7a is required for recruitment of the retromer CSC and as a GTPase, its activity is regulated by specific GEFs and GAPs making it more amenable to modulation of its activity than Snx3 (Pfeffer, 2017). A good candidate for a Rab7a GAP is the TBC1D5 protein (Jia et al., 2016), and studies in nematode have supported a role for TBC1D5 in regulating the worm equivalent of Rab7a (Mukhopadhyay et al., 2007). Therefore, we investigated whether loss of TBC1D5 could boost the levels of retromer associated with endosomes and thereby enhance retromer function. Here, we report that loss of TBC1D5 does elevate the levels of GTP-bound Rab7a, increasing the association of the retromer CSC with endosomes. This leads to an enhanced interaction of retromer with accessory factors such as the WASH complex and can rescue the effect of the PD-causing VPS35 D620N mutant, generating a gain-of-function phenotype with respect to processing of APP to Aβ.
