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OIP106 (TRAK1) and GRIF-1 (TRAK2) kinesin-associated adaptor proteins: a study of their role in mitochondrial trafficking processes in neurones

Reference	BB/E021549/1
Principal Investigator / Supervisor	Professor Frances Stephenson
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Pharmaceutical and Biological Chem
Funding type	Research
Value (£)	400,199
Status	Completed
Type	Research Grant
Start date	25/05/2007
End date	24/05/2010
Duration	36 months

Abstract

An emerging feature of trafficking mechanisms in neurones is that the transport of proteins and/or organelles occurs via adaptor proteins that link kinesin motor proteins to their cargoes. My research group discovered and cloned a protein, GRIF-1 (TRAK2), that we have recently shown is an example of a kinesin associated adaptor protein. GRIF-1 and the homologue, OIP106 (TRAK1), are members of a novel coiled-coil gene family. Whilst we originally proposed that GRIF-1 was involved in trafficking inhibitory GABA-A neurotransmitter receptors, it appears that both proteins may play a more general role in trafficking in excitable tissues. In this proposal, we wish to study in more detail this family of adaptor proteins. The impetus for the experiments described herein has come from our previous work and also, from the recent work describing the Drosophila orthologue of GRIF-1 and OIP106, Milton. Milton is purported to play a role in the trafficking of mitochondria in neurones. We have shown that both GRIF-1 and OIP106, like Milton, aggregate mitochondria, that this aggregation is mediated via the C-terminal, non-KHC binding domain of GRIF-1 and that in heterologous systems, mitochondria are trafficked in a GRIF-1 mediated kinesin-1-dependent manner. Here we plan to investigate the role of both GRIF-1 and OIP106 in mitochondrial trafficking by identifying mitochondrial partners of GRIF-1 and OIP106; by studying the transport of mitochondria via siRNA gene knock-down experiments, how this may be regulated via post-translational modification mechanisms and determining the cargoes that the KHC/GRIF-1 or KHC/OIP106 complexes transport. Results from the proposal will yield fundamental information on trafficking processes in neurones that may impact in the long term on the understanding of neurodegenerative disorders.

Summary

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. 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. 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-1and 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.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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