is worth noting, however, that increased Atg9a and TGN46 colocalisation is not statistically significant in cells expressing the VPS35 D620N mutant that causes impaired Atg9a trafficking (Zavodszky et al., 2014). Not all retromer cargo proteins respond to TBC1D5 knockdown equally and in cells expressing CD8-SorL1, we observed that loss of TBC1D5 expression very modestly reduced the colocalisation of the CD8-SorL1 reporter with TGN46 (see Fig. S2). Secondly, we tested whether loss of TBC1D5 expression could alter the processing of APP to Aβ. It has been shown previously that knockdown of VPS35 increases processing of APP to Aβ (Muhammad et al., 2008) and we find this also. In cells where TBC1D5 has been silenced, we observed a reduction in the levels of Aβ secreted into the medium and lower levels of sAPPβ, consistent with enhanced retromer function (Fig. 6C,D).
