Heterotrimeric kinesin‐2, together with kinesin‐1, steers vesicular acetylcholinesterase movements toward the synapse

Abstract

Acetylcholinesterase (AChE), which is implicated in the pathophysiology of neurological disorders, is distributed along the axon and enriched at the presynaptic basal lamina. It hydrolyses the neurotransmitter acetylcholine, which inhibits synaptic transmission. Aberrant AChE activity and ectopic axonal accumulation of the enzyme are associated with neurodegenerative disorders, such as Alzheimer's disease. The molecular mechanism that underlies AChE transport is still unclear. Here, we show that expression of AChE tagged with photoactivatable green fluorescent protein and-Cherry (GPAC) in cholinergic neurons compensates for the RNA interference-mediated knockdown of endogenous AChE activity. GPAC-AChE, which is enriched in the neuropil region of the brain, moves in the apparently vesicular form in axons with an anterograde bias in larvae. Two anterograde motors, kinesin-1 and -2, propel distinct aspects of GPAC-AChE movements. Total loss of kinesin-2 reduces the density of anterograde traffic and increases bidirectional movements of GPAC-AChE vesicles without altering their speed. A partial loss of kinesin-1 reduces both the density and speed of anterograde GPAC-AChE traffic and enhances the pool of stationary vesicles. Together, these results suggest that combining activity of a relatively weak kinesin-2 with that of a stronger kinesin-1 motor could steer AChE-containing vesicles toward synapse, and provides a molecular basis for the observed subcellular distribution of the enzyme.-Kulkarni, A., Khan, Y., Ray, K. Heterotrimeric kinesin-2, together with kinesin-1, steers vesicular acetylcholinesterase movements toward the synapse.

Anterograde Transport of Rab4-Associated Vesicles Regulates Synapse Organization in Drosophila

“…These vesicles predominantly move towards the synapse in axons. Although Kinesin-2 is also found to bind and transport vesicles containing Acetylcholinesterase in the same axon (Kulkarni et al, 2016), we observed that Rab4 does not mark them. Similarly, the post-Golgi vesicles carrying N-Cadherin and β-Catenin, which are known to associate with Kinesin-2 (Hirokawa et al, 2009), exclude Rab4.…”

“…In a recent study, it was shown that combined activities of Kinesin-1 and 2 steers the AChE containing vesicles in the axon (Kulkarni et al, 2016). A simultaneous association of these two motors was suggested to induce longer runs of the AChE containing vesicles.…”

Autoinhibition of kinesin-1 is essential to the dendrite-specific localization of Golgi outposts

“…While this kinesin could be kinesin-1 itself, it is also possible that an additional kinesin is involved in transporting outposts. The best candidates for such another kinesin would be kinesin-2 or kinesin-3, which co-transport some cargo with kinesin-1 (Guardia et al, 2016;Gumy et al, 2017;Hendricks et al, 2010;Kulkarni et al, 2017;Lim et al, 2017;Ruane et al, 2016).…”

Two kinesins drive anterograde neuropeptide transport

“…Models of axonal transport for individual types of organelles have largely focused on one anterograde kinesin type. However, some transport mechanisms can employ more than one kinesin type ( Hendricks et al , 2010 ; Guardia et al , 2016 ; Kulkarni et al , 2017 ). For example, in Drosophila axons, there is evidence that kinesin-1 and kinesin-2 both influence the transport and distribution of acetylcholine (ACh) esterase vesicles ( Kulkarni et al , 2017 ).…”