Guy Tear

Guy Tear

Professor

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Research interests

My research is based on the need to understand the genetic mechanisms that control the establishment of the circuitry of the nervous system and for insights into the normal and pathological function of proteins that contribute to neurodegenerative disease. Through a better knowledge of how neural development normally occurs and how neurodegenerative pathologies develop we hope to provide information to aid neural regrowth and combat neural disease and injury.

During development, growing axons are guided to their appropriate targets by extracellular cues, the response to which depends crucially on the repertoire of receptors expressed by each axon and the intracellular mechanisms that transduce and regulate the response to these cues. In the past ten-fifteen years this research area has been significantly advanced by the identification of several major families of guidance cues and their cognate receptors and the elucidation of many aspects of the molecular mechanisms of axon guidance.

My group has played a significant role in these discoveries, notably we contributed to the original discovery of the highly conserved Roundabout family of receptors and have revealed important aspects of their regulation. However, globally we still have only a rudimentary understanding of how these axon guidance processes are coordinated to specify the precise wiring of billions of cells in thousands of tracts in the brain. To fully understand this process it will be necessary to identify additional genes involved in wiring, define their expression patterns over the course of development and elucidate their cellular functions and molecular interactions.

My group has identified further molecules that may contribute to the development of the nervous system (Dolan et al., 2007; Araujo et al., 2005; Wakefield and Tear, 2006; Alsbury et al., unpub obs) and identified intracellular regulatory mechanisms (Gogel et al., 2007; van den Brink et al., unpub. obs) which are adding to the study of the molecular mechanisms that regulate the development of connectivity in the embryonic central nervous system (CNS) of Drosophila.

In addition my research group has developed the use of Drosophila as a model system to identify the normal and pathological roles of proteins associated with neurodegenerative disease. We have built collaborations with groups at the Institute of Psychiatry to investigate elements of Alzheimer's and Batten disease. The Alzheimer's work has focused on the critical role played by Tau hyperphosphorylation in Alzheimer's disease pathology where it has become clear that a small number of kinases are responsible for the majority of the phosphorylation sites on tau in AD brain. We have established Drosophila as a whole animal assay to investigate which of these are responsible for the generation of toxic forms of tau in vivo. This makes use of humanised Drosophila that express human tau and specific identified human kinases to create an AD-like pathology. Using this system we are beginning to discriminate the specific involvement of the different kinases alone or together in the creation of toxic forms of tau.

Batten disease or the neuronal ceroid lipofuscinoses (NCLs) descibes a group of at least nine fatal monogenetic neurodegenerative disorders that primarily affect infants and children. The genes mutated in several forms of the disorder have been identified recently, but very little is known about the precise roles of these gene products in normal neuronal tissue and how their mutation contributes to the disease. We have begun to combat this by investigating the role of the transmembrane protein Cln3, which is affected in the most common form of NCL, using Drosophila. We have identified that the Drosophila Cln3 shares many properties with the vertebrate form, it is localised to the endosomal-lysosomal compartment in many cell type and found at the synapse.

By manipulating Cln3 function in Drosophila we have identified that it interacts with Notch and JNK signalling (Tuxworth et al.,2009) and increases in its activity interferes with the normal function and development of the neuromuscular junction (Tuxworth et al unpub obs).

We are also near completion of a large scale screen to identify genes that modify Cln3 activity and this has provided us with a significant amount of information on the possible molecular pathways that are affected by changes in Cln3 activity.

Research interests (short)

Drosophila as a model system to study axonal guidance and neurodegenerative disease.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

Doctor of Philosophy, A molecular analysis of embryonic development in the short germ band insect, Schistocerca gregaria, University of Cambridge

Award Date: 1 Jan 1990

Bachelor of Arts, University of Cambridge

Award Date: 1 Jan 1986

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