# Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2bintron5

## TL;DR

This study shows how a mutation in CHMP2b disrupts its transport in neurons, leading to presynaptic dysfunction linked to frontotemporal dementia.

## Contribution

The study identifies kinesin-binding protein as a regulator of CHMP2b transport and reveals how the CHMP2bintron5 mutation disrupts this process.

## Key findings

- CHMP2b transport and synaptic localization are regulated by neuronal activity and kinesin-binding protein.
- The CHMP2bintron5 mutation causes abnormal transport and synaptic mislocalization of CHMP2b.
- Deficient binding to kinesin-binding protein explains the disrupted transport of CHMP2bintron5.

## Abstract

This study investigates the axonal trafficking of the ESCRT-III protein CHMP2b and shows how the frontotemporal dementia–causative CHMP2bintron5 mutation disrupts its transport and synaptic localization.

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 CHMP2bintron5 mutation exhibits little processive movement or presynaptic localization in the presence or absence of neuronal activity. Instead, CHMP2bintron5 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 CHMP2bintron5 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 CHMP2bintron5.