Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein.
Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein.
复制标题
应力诱导的CDK5激活通过LIS1/NDEL1/DYNEIN破坏轴突转运。
DOI：
10.1016/j.celrep.2015.06.032
复制
发表时间：
2015-07-21
期刊：
影响因子：
8.8
通讯作者：
Holzbaur EL
中科院分区：
文献类型：
--
作者：
Klinman E;Holzbaur EL
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.
