Figure 2.

Proposed models of pathogenic mechanism. Under normal conditions, Rab5 and Rab7 deliver trophic signals to the soma under tight regulation. Upon delivery of the signal, Rab5-positive early endosomes transition to late endosomes/lysosomes facilitated by Rab7 (A). In CMT2B, hyperactive Rab7 vesicles with greater affinity for downstream effectors could travel at faster anterograde speeds, resulting in premature fusion and degradation of signal-carrying Rab5 endosomes (B). Alternatively, hyperactivation of Rab7 vesicles could lead to aggregation of late endosomes/lysosomes near the nucleus and in the axon, consequently blocking trophic signals from reaching the soma (C).