| First Author | Klinman E | Year | 2015 |
| Journal | Cell Rep | Volume | 12 |
| Issue | 3 | Pages | 462-73 |
| PubMed ID | 26166569 | Mgi Jnum | J:224838 |
| Mgi Id | MGI:5689193 | Doi | 10.1016/j.celrep.2015.06.032 |
| Citation | Klinman E, et al. (2015) Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein. Cell Rep 12(3):462-73 |
| abstractText | 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. |
