OIP106 (TRAK1) and GRIF-1 (TRAK2), kinesin-associated adaptor proteins: a study of their role in mitochondrial trafficking processes in neurons.
Funded by BBSRC
Prof. A. Stephenson
Information in our brains is processed by a discontinuous network of nerve cells or neurones. Communication between these cells occurs at specialized regions called synapses that are found at axon terminals. Synapses are metabolically dynamic and energy sources and proteins need to be constantly replenished to ensure fidelity of brain function. Since the synapse is often distant from the neuronal cell body (it can be up to 1 metre away), newly synthesized proteins need to be transported to these active zones. This transport process is achieved by motor proteins that associate with their cargoes via adaptor proteins that travel along the microtubular network within the neurones.
A schematic diagram depicting putative GRIF-1 (TRAK2) -kinesin-cargo interactions for the anterograde trafficking of defined cargoes to synapses. (Adapted from Smith, M.J., Pozo, K., Brickley, K. and Stephenson, F.A. (2006) J. Biol. Chem. 281, 27216-27228. Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes.)
My research group discovered a protein, GABA-A Receptor Interacting Factor-1 (GRIF-1, also called TRAK2), a member of a new gene family that is integral to these transport processes. The name derives from GRIF-1's first identified functional role in the transport of inhibitory GABA-A neurotransmitter receptor proteins to synapses but, it is now thought to play a more general role in neuronal trafficking processes since it has been shown to associate with the motor protein, kinesin. In flies, often used as model organisms, researchers have identified a protein that is similar to GRIF-1. This protein is called Milton. The name derives from the blind poet, John Milton; flies that do not have Milton are blind. In these mutant flies, it was found that mitochondria, a subcomponent of the cell that supplies energy, are absent from synapses in the neurones in the eyes of flies.
Over-expression of GRIF-1 (TRAK2) in COS-7 cells results in mitochondrial aggregation
It was thus speculated that Milton plays an important role in the trafficking of these organelles to synapses to supply energy for the proper communication between adjacent neurones. In this research proposal, we wish to study the role of GRIF-1 (TRAK2) and the related protein OIP106 (TRAK1) in model cell systems and in neurones to test if they have a similar function to Milton; to identify which mitochondrial proteins GRIF-1 and OIP106 bind and to determine how their activities are regulated. A deficiency in trafficking mechanisms may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease and spasticity. Thus, if we understand these basic mechanisms, in the future it may be possible to contribute towards the development of innovative therapies for their treatment..
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