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

Cell Rep. 2015 Jul 21;12(3):462-73. doi: 10.1016/j.celrep.2015.06.032. Epub 2015 Jul 9.


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, also is 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Axonal Transport / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Disease Models, Animal
  • Dyneins / metabolism*
  • Endosomes / metabolism
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Neurons / metabolism


  • Carrier Proteins
  • Microtubule-Associated Proteins
  • NDEL1 protein, human
  • Ndel1 protein, mouse
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Cdk5 protein, mouse
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human
  • Pafah1b1 protein, mouse
  • Dyneins