RRC ID 36009
Author Klinman E, Holzbaur EL.
Title Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein.
Journal Cell Rep
Abstract 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.
Volume 12(3)
Pages 462-73
Published 2015-7-21
DOI 10.1016/j.celrep.2015.06.032
PII S2211-1247(15)00644-0
PMID 26166569
PMC PMC4532378
MeSH 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
IF 8.109
Times Cited 34
Mice RBRC00806