What do we know:
Cargos move up and down axons normally, and this is disrupted when axons become stressed or ill (like in ALS, Alzheimer’s, and Parkinson’s).
What don’t we know: We don’t understand what regulates the movement along the axon (what controls the motor proteins dynein and kinesin), and how we can fix this process when it goes wrong.
What this study shows: This study shows how CDK5 over-activation causes disrupted cargo transport through changes in motor protein activity. CDK5 alters motor proteins indirectly, through proteins Ndel1 and Lis1. Reducing CDK5 activity restores cargo transport to normal in mouse models of ALS.
What we can do in the future because of this study: We can figure out what else is affecting cargo transport in neurons (it isn’t just CDK5!), and in the future attempt to treat sick mice by reducing CDK5 to see if they live longer.
Why you should care: Understanding how tiny cargo move in neurons is awesome! Also, if we can figure out how disrupted cargo transport contributes to disease, we can develop better treatments.
Neurons are the longest cells in the body, with axons that can stretch from your spine to your foot. Proteins and organelles made in the cell body need to be transported to the end of the axon (led by the motor protein kinesin), and old organelles need to be transported back up the axon to be degraded (dragged along behind the motor protein dynein). This transport up and down the axon is disrupted in neurodegenerative diseases like ALS, Alzheimer’s, and Parkinson’s. Scientists do not know how exactly transport is being disrupted, or what we can do to fix it. We found that a neuronal-specific kinase, CDK5, which is over-activated in all of these diseases, is responsible for disrupting transport. High activity of CDK5 causes organelles to wiggle back-and-forth rather than moving smoothly. However, this kinase does not phosphorylate either motor protein directly, rather, we found that it acts on Ndel1, a protein which binds another protein (Lis1) to interfere with dynein-drive transport from the end of the axon to the cell body. Therefore, CDK5 acts indirectly to disrupt transport. Reducing CDK5 activity in neurons from an ALS mouse model helped restore transport.
Axonal transport is disrupted in neurodegenerative disease, but we don’t know how transport is regulated in healthy or diseased neurons. The kinase CDK5 is overactivated in stressed neurons because its normal activator (p35, membrane bound) is cleaved (p25, membrane-free), and this cleavage product is spatially and temporally deregulated. We found that expressing the stress activator (p25) in healthy neurons caused disruption of transport for a wide range of cargos including lysosomes, autophagosomes, mitochondria, and signaling endosomes. Previous labs have determined that CDK5 does not directly phosphorylate kinesin or dynein. However, we determined that CDK5 phosphorylates Ndel1, which binds Lis1 to regulate the retrograde processivity of dynein. Without Ndel1, CDK5 cannot disrupt motility. Moreover, similar disruptions are found in neurons taken from SOD1 mice, an ALS mouse model. Reducing CDK5 activity in these neurons returns transport to normal, implying that CDK5 over-activity is responsible for disrupting transport.