Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein

Abstract

Summary Axonal transport is essential for neuronal function, and defects in transport are associated with multiple neurodegenerative diseases. Aberrant cyclin dependent kinase 5 (CDK5) activity, driven by the stress-induced activator p25, is also observed in these diseases. Here, we show that elevated CDK5 activity increases the frequency of nonprocessive events for a range of organelles including lysosomes, autophagosomes, mitochondria, and signaling endosomes. Transport disruption induced by aberrant CDK5 activation depends on the Lis1/Ndel1 complex, which directly regulates dynein activity. CDK5 phosphorylation of Ndel1 favors a high affinity Lis1/Ndel/dynein complex that blocks the ATP-dependent release of dynein from microtubules, inhibiting processive motility of dynein-driven cargo. Similar transport defects observed in neurons from a mouse model of Amyotrophic Lateral Sclerosis are rescued by CDK5 inhibition. Together, these studies identify CDK5 as a Lis1/Ndel1-dependent regulator of transport in stressed neurons, and suggest that dysregulated CDK5 activity contributes to the transport deficits observed during neurodegeneration.

Regulation of Axonal Transport by Protein Kinases

“…In this study, expression of kinase-dead Cdk5 did not affect the axonal transport of lysosomes, mitochondria, or TrkB-containing endosomes [75], suggesting that Cdk5 does not play a role in the regulation of axonal transport under normal conditions. By contrast, increasing Cdk5 activity disrupted the axonal transport of these cargoes [75], suggesting that Cdk5 modulates axonal transport only under cellular stress. Although the reason for these conflicting results is unclear, it may be related to differences in the protocol used for DRG isolation and maintenance [72,75].…”

“…By contrast, increasing Cdk5 activity disrupted the axonal transport of these cargoes [75], suggesting that Cdk5 modulates axonal transport only under cellular stress. Although the reason for these conflicting results is unclear, it may be related to differences in the protocol used for DRG isolation and maintenance [72,75].…”

CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

“…CDK5 has many known functions in neurons, including dendritic development, 20 neuronal migration, 21 axonal guidance, 22 and organelle transport. 23–27 Previous work has shown that CDK5 activates dynein indirectly, through phosphorylation of Ndel1, which controls dynein activity in conjunction with the dynein-binding protein Lis1. 25 …”

“…Phosphorylation of Ndel1 by CDK5 results in the formation of a phospho-Ndel1/Lis1 complex 27 ; the binding of Lis1 to the dynein motor domain within this complex results in steric blockade of the dynein powerstroke. 28 This leaves dynein unable to release from the microtubule even when ATP is bound.…”

“…Strong binding of this phospho-Ndel1/Lis1/dynein complex to the microtubule interrupts processive cargo transport in the mid-axon. 27 This Lis1-dependent mechanism is required for the effective initiation of retrograde transport, likely enhancing the initial recruitment of dynein to the microtubule. 29 Intriguingly, Ndel1 was recently found to localize preferentially to the AIS.…”