Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2b(intron5).

CHMP2b is a core component of the ESCRT pathway that catalyzes formation of multivesicular bodies for endolysosomal protein degradation. Although mutation/loss-of-function of CHMP2b promotes presynaptic dysfunction and degeneration, indicating its critical role in presynaptic protein homeostasis, the mechanisms responsible for CHMP2b localization and recruitment to synapses remain unclear. Here, we characterize CHMP2b axonal trafficking and show that its transport and recruitment to presynaptic boutons, as well as its cotransport with other ESCRT proteins, are regulated by neuronal activity. In contrast, the frontotemporal dementia-causative CHMP2b(intron5) mutation exhibits little processive movement or presynaptic localization in the presence or absence of neuronal activity. Instead, CHMP2b(intron5) transport vesicles exhibit oscillatory behavior reminiscent of a tug-of-war between kinesin and dynein motor proteins. We show that this phenotype is caused by deficient binding of CHMP2b(intron5) to kinesin-binding protein, which we identify as a key regulator of CHMP2b transport. These findings shed light on the mechanisms of CHMP2b axonal trafficking and synaptic localization, and their disruption by CHMP2b(intron5).