Endocannabinoids modulate growth cone dynamics and axonal pathfinding through the stimulation of cannabinoid type-1 receptors (CB1R) which function depends on its delivery and precise presentation at the growth cone surface. However, the mechanism involved in the axonal transport of CB1R and its role in eCB signaling remains elusive. Kinesin-1 mutations have been identified in patients with abnormal cortical development and impaired white matter integrity. We found defects in axonal pathfinding and fasciculation in mice lacking the kinesin light chain 1 (KLC1−/−) subunit of the kinesin-1 molecular motor. Reduced levels of CB1R were observed in corticofugal projections and growth cones in KLC1−/−. By live-cell imaging of CB1R-eGFP we characterized the axonal transport of CB1R vesicles in control conditions and the defects in transport that arise in KLC1 deleted neurons. Cofilin activation, which is necessary for actin dynamics during growth cone remodeling, is impaired in KLC1−/− cortex. KLC1−/− neurons showed expanded growth cones that resulted unresponsive to CB1R-induced axonal elongation. Together, our data reveal the relevance of kinesin-1 in CB1R axonal transport and in endocannabinoid signaling during brain wiring.

Alzheimer disease (AD) pathology includes the accumulation of poly-ubiquitylated (also known as poly-ubiquitinated) proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. By using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescence cross-correlation analyses and membrane internalization blockage experiments showed that plasma membrane APP does not contribute to transport defects. Moreover, by western blotting and double-color APP imaging, we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery, where β-cleavage is induced. Taken together, we found that proteasomes control the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates the intracellular APP dynamics, and defects in proteasome activity can be considered a contributing factor that leads to abnormal APP metabolism in AD.This article has an associated First Person interview with the first author of the paper.

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