Hugh Bennett, PhD
progranulin • zebrafish • motor neuron development • protein structure and function • high-performance liquid chromatography (HPLC)
My research focuses upon defining the mechanism of action of progranulin and understanding the role that it plays in human physiology and pathophysiology. Progranulin is a growth factor critically involved in the development of many tissues including neurons. Mutation of the progranulin gene leads to the appearance of an early onset form of frontotemporal dementia in human patients. We have shown the zebrafish genome encodes several distinct forms of progranulin that collectively serve the functions of the single human progranulin gene. Knockdown of zebrafish progranulin gene expression leads to the disturbance of normal development of motor neurons. This can be rescued by the expression of exogenous progranulin. Through the use of cell culture techniques and exploitation of the zebrafish model we will better define the mechanism of action of progranulin. This in turn will facilitate the design of novel compounds and therapies with potential in the treatment of neurodegenerative diseases.
Bateman, A. and Bennett, H.P.J. The granulin gene family: from cancer to dementia. BioEssays, 31,1245-1254, 2009 PMID: 19795409.
Ryan, C., Baranowski, D., Chitramuthu, B., Malik, S.M., Li, Z., Cao, M.J., Minotti, S., Durham, H.D., Kay, D., Shaw, C.A., Bennett, H.P.J. and Bateman, A. Progranulin is expressed within motor neurons of the mouse spinal cord and promotes neuronal cell survival. BMC-Neuroscience, 10, 130, 2009 PMID: 19860916.
Chitramuthu, B.P., Baranowski, D., Cadieux, B., Rousellet, E., Seidah, N.G. and Bennett, H.P.J Molecular cloning and embryonic expression of zebrafish PC5 co-orthologues; Functional assessment during lateral line development. Developmental Dynamics, 239, 2933-2946, 2010 PMID: 20882679.
Progranulin modulates zebrafish motoneuron development and is neurotrophic in vivo. Chitramuthu, B.P., Baranowski, D.C., Kay D.G., Bateman, A., and Bennett, H.P.J. Molecular Neurodegeneration, 5, 41, 2010 PMID: 20946666.
Tauffenberger, A., Chitramuthu, B.P., Bateman, A., Bennett, H.P.J. and Parker, J.A. Reduction of polyglutamine toxicity by TDP-43, FUS and Progranulin in Huntington's Disease models. Hum. Mol. Genet., 22, 782-794, 2013.