Lemur tyrosine kinase-2 and axonal transport of cdk5/p35 and protein phosphatase-1

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The abilities of our brains to compute information is linked to the numbers of connections that individual brain neuron cells make with one another. These connections are termed synapses and it is estimated that a human brain contains 100-500 trillion synapses. Loss of synapses occurs as we age and pathogenic synaptic loss is believed be the underlying cause of dementia in Alzheimer's disease. The mechanisms by which synapses are lost in ageing and disease are not properly understood but one suggestion is that it involves, at least in part, defects to the delivery of essential proteins and other components to the synapse. Most synaptic proteins are synthesized in a different part of the neuron cell and so have to be transported to synapses. One type of transport is termed axonal transport and this involves moving protein cargoes through the long axon processes of neurons. This movement involves "molecular motor proteins" and these run on rails called microtubules and utilize a fuel called ATP. Axonal transport is therefore like a train journey with a motor or engine that requires a fuel and runs on rails. Cyclin dependent kinase-5/p35 (Cdk5/p35) and protein phosphatase-1 (PP1) are two major protein complexes that perform a number of essential functions in the synapse. Moreover, disruption to cdk5/p35 and PP1 functions are linked to Alzheimer's and other neurodegenerative diseases. However, the mechanisms by which these important proteins are transported to the synapse are not known. We have shown that cdk5/p35 and PP1 both bind to another protein called lemur tyrosine kinase-2 (LMTK2) and that LMTK2 attaches to a molecular motor called kinesin-1. Thus, cdk5/p35 and PP1 may be transported to synapses on kinesin-1 motors via their attachment to LMTK2. The Aim of this project is to test this possibility. The objectives are:-1. To finalise our studies demonstrating that LMTK2 scaffolds cdk5/p35 and PP1 to KLCs.2. To properly characterise axonal transport of LMTK2.3. To study the role of LMTK2 on axonal transport of cdk5/p35 and PP1. 4. To investigate the mechanisms that regulate axonal transport of the LMTK2-cdk5/p35-PP1 complexThe study will provide important information on fundamental neurophysiological processes. In addition, since damage to axonal transport and to cdk5/p35 and PP1 synaptic functions are all seen in Alzheimer's and related diseases, the work may reveal new targets for therapeutic intervention for these disorders.