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Health Sciences profile

Associate Professor Stephanie Hughes

PositionAssociate Professor
DepartmentDepartment of Biochemistry
QualificationsBSc(Hons) PhD
Research summaryNeural Development and Disease

Research

Neurodegenerative and Lysosomal disease laboratory (NLD)

We are interested in the molecular and cellular processes in neurodegenerative disease, in particular how lysosome dysfunction influences disease processes. A better understanding of these processes helps us to develop relevant model systems in which we aim to find new therapeutic targets and test treatments.

The Hughes Lab

The Hughes laboratory group

BATTEN DISEASE

Developing models of childhood Batten disease

We work on a childhood brain disease called Batten disease. In Batten disease, the recycling machinery in neurons goes haywire, which leads to death of the neurons. We aim to understand what leads to the malfunctioning of the recycling system and how to rectify the faults, leading to treatment options that can rescue dying neurons. We use reprogrammed skin cells, which get differentiated into human neurons. Using these cells we take advantage of gene therapy techniques to manipulate gene expression and develop our models.

Induced pluripotent stem cells are used to model Batten disease

Induced pluripotent stem cells are used to model Batten disease

Indranil Basak, Postdoctoral fellow
Janet Boyu Xu, Postdoctoral fellow
Oluwatobi Eboda, PhD student
Jennifer Palmer, Honours student

Expression of Batten CLN5 in sheep brain cells

Expression of Batten CLN5 in sheep brain cells

Funded from Cure Kids New Zealand and the Neurological Foundation of New Zealand

Cellular waste disposal in brain diseases

The lysosome is essential for removing cellular waste and its dysfunction is a common feature of neurodegenerative diseases. When people think of the brain cells they think of neurons, but there are also the glial cells, commonly referred to as support cells, that play a critical role in neuronal health and activity. Through the use of animal models and cell lines our research aims to determine how glial lysosome function impacts neuronal health. In addition, we are screening drugs that work to enhance lysosome function in Batten disease and test new gene therapy strategies.

Lucia Schweitzer, Research fellow
Hollie Wicky, Assistant research fellow
Jasmine Lock, PhD student

Induced pluripotent stem cell derived neurons

Induced pluripotent stem cell derived neurons

Funded by the Health Research Council of New Zealand and the Charlotte and Gwyneth Gray Foundation Cure Batten, USA

ALZHEIMERS DISEASE

We are interested in a protein called sAPPα which has memory enhancing, neurogenic and neuroprotective properties. Our research aims to increase our knowledge of its mechanisms of action, by identifying other genes and proteins that are involved in these processes. We hypotheise that sAPPα has therapeutic potential for Alzheimers disease.

Katie Peppercorn, PhD student (with Professor Warren Tate)

Gene therapy

We are establishing a new non-invasive treatment of Alzheimers disease (AD). Using peripheral gene therapy, we are focusing on treatments which cross the brain barrier more efficiently. Our aim is to reduce synaptic dysfunction and rescue spatial memory in peripherally gene therapy treated AD mouse models.

Sophie Mathiesen, PhD student (with Professor Cliff Abraham)
Yuanyuan (Emily) He, PhD student (with Professor Cliff Abraham)

Much of our work relies on gene therapy vectors such as lentivirus and adeno-associated virus, which we package in the Otago Viral Vector Facility with support from Brain Research New Zealand.

Kirstin McDonald, Assistant research fellow

Funded by the Health Research Council of New Zealand and Brain Research New Zealand

Human neurons express the amyloid precursor protein (APP; red)

Human neurons express the amyloid precursor protein (APP; red)

Comparing AAV serotypes (green and red) in the mouse heart

Comparing AAV serotypes (green and red) in the mouse heart

Comparing AAV serotypes (green and red) in the mouse spinal cord

Comparing AAV serotypes (green and red) in the mouse spinal cord

AAV gene therapy (green) in the mouse cerebral cortex

AAV gene therapy (green) in the mouse cerebral cortex

Publications

Cain, J. T., Likhite, S., White, K. A., Timm, D. J., Davis, S. S., Johnson, T. B., … Hughes, S. M., … Weimer, J. M. (2019). Gene therapy corrects brain and behavioral pathologies in CLN6-Batten disease. Molecular Therapy. Advance online publication. doi: 10.1016/j.ymthe.2019.06.015

Schoderboeck, L., Wicky, H. E., Abraham, W. C., & Hughes, S. M. (2019). Genetic targeting and chemogenetic inhibition of newborn neurons. Human Gene Therapy Methods, 29(6), 259-268. doi: 10.1089/hgtb.2018.182

Huber, R. J., Hughes, S. M., Liu, W., Morgan, A., Tuxworth, R. I., & Russell, C. (2019). The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research. Biochimica et Biophysica Acta: Molecular Basis of Disease. Advance online publication. doi: 10.1016/j.bbadis.2019.165614

Morrissey, J. A., Mockett, B. G., Singh, A., Kweon, D., Ohline, S. M., Tate, W. P., Hughes, S. M., & Abraham, W. C. (2019). A C-terminal peptide from secreted amyloid precursor protein-α enhances long-term potentiation in rats and a transgenic mouse model of Alzheimer's disease. Neuropharmacology, 157, 107670. doi: 10.1016/j.neuropharm.2019.107670

Morrissey, J. A., Bigus, E., Necarsulmer, J. C., Srinivasan, V., Peppercorn, K., O'Leary, D. J., Mockett, B. G., Tate, W. P., Hughes, S. M., … Abraham, W. C. (2019). The tripeptide RER mimics secreted amyloid precursor protein-alpha in upregulating LTP. Frontiers in Cellular Neuroscience, 13, 459. doi: 10.3389/fncel.2019.00459

Chapter in Book - Research

Empson, R. M., Tantirigama, M. L. S., Oswald, M. J., Hughes, S. M., & Knöpfel, T. (2015). Combined immunochemistry and live imaging of fluorescent protein expressing neurons in mouse brain. In A. Merighi & L. Lossi (Eds.), Immunocytochemistry and related techniques. (pp. 357-373). New York: Springer. doi: 10.1007/978-1-4939-2313-7_19

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Journal - Research Article

Cain, J. T., Likhite, S., White, K. A., Timm, D. J., Davis, S. S., Johnson, T. B., … Hughes, S. M., … Weimer, J. M. (2019). Gene therapy corrects brain and behavioral pathologies in CLN6-Batten disease. Molecular Therapy. Advance online publication. doi: 10.1016/j.ymthe.2019.06.015

Morrissey, J. A., Bigus, E., Necarsulmer, J. C., Srinivasan, V., Peppercorn, K., O'Leary, D. J., Mockett, B. G., Tate, W. P., Hughes, S. M., … Abraham, W. C. (2019). The tripeptide RER mimics secreted amyloid precursor protein-alpha in upregulating LTP. Frontiers in Cellular Neuroscience, 13, 459. doi: 10.3389/fncel.2019.00459

Morrissey, J. A., Mockett, B. G., Singh, A., Kweon, D., Ohline, S. M., Tate, W. P., Hughes, S. M., & Abraham, W. C. (2019). A C-terminal peptide from secreted amyloid precursor protein-α enhances long-term potentiation in rats and a transgenic mouse model of Alzheimer's disease. Neuropharmacology, 157, 107670. doi: 10.1016/j.neuropharm.2019.107670

Huber, R. J., Hughes, S. M., Liu, W., Morgan, A., Tuxworth, R. I., & Russell, C. (2019). The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research. Biochimica et Biophysica Acta: Molecular Basis of Disease. Advance online publication. doi: 10.1016/j.bbadis.2019.165614

Schoderboeck, L., Wicky, H. E., Abraham, W. C., & Hughes, S. M. (2019). Genetic targeting and chemogenetic inhibition of newborn neurons. Human Gene Therapy Methods, 29(6), 259-268. doi: 10.1089/hgtb.2018.182

Tan, V. T. Y., Mockett, B. G., Ohline, S. M., Parfitt, K. D., Wicky, H. E., Peppercorn, K., Schoderboeck, L., Yahaya, M. F. b., Tate, W. P., Hughes, S. M., & Abraham, W. C. (2018). Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease. Molecular Brain, 11, 7. doi: 10.1186/s13041-018-0348-9

Ohline, S. M., Wake, K. L., Hawkridge, M.-V., Dinnunhan, M. F., Hegemann, R. U., Wilson, A., Schoderboeck, L., Logan, B. J., … Hughes, S. M., & Abraham, W. C. (2018). Adult-born dentate granule cell excitability depends on the interaction of neuron age, ontogenetic age and experience. Brain Structure & Function, 223(7), 3213-3228. doi: 10.1007/s00429-018-1685-2

Mitchell, N. L., Russell, K. N., Wellby, M. P., Wicky, H. E., Schoderboeck, L., Barrell, G. K., Melzer, T. R., … Hughes, S. M., & Palmer, D. N. (2018). Longitudinal in vivo monitoring of CNS demonstrates the efficacy of gene therapy in a sheep model of CLN5 Batten disease. Molecular Therapy, 26(10), 2366-2378. doi: 10.1016/j.ymthe.2018.07.015

Clare, A. J., Day, R. C., Empson, R. M., & Hughes, S. M. (2018). Transcriptome profiling of layer 5 intratelencephalic projection neurons from the mature mouse motor cortex. Frontiers in Molecular Neuroscience, 11, 410.

Clare, A. J., Wicky, H. E., Empson, R. M., & Hughes, S. M. (2017). RNA-sequencing analysis reveals a regulatory role for transcription factor Fezf2 in the mature motor cortex. Frontiers in Molecular Neuroscience, 10, 283. doi: 10.3389/fnmol.2017.00283

Best, H. L., Neverman, N. J., Wicky, H. E., Mitchell, N. L., Leitch, B., & Hughes, S. M. (2017). Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics. Neurobiology of Disease, 100, 62-74. doi: 10.1016/j.nbd.2017.01.001

Sizemore, R. J., Seeger-Armbruster, S., Hughes, S. M., & Parr-Brownlie, L. C. (2016). Viral vector-based tools advance knowledge of basal ganglia anatomy and physiology. Journal of Neurophysiology, 115, 2124-2146. doi: 10.1152/jn.01131.2015

Tantirigama, M. L. S., Oswald, M. J., Clare, A. J., Wicky, H. E., Day, R. C., Hughes, S. M., & Empson, R. M. (2016). Fezf2 expression in layer 5 projection neurons of mature mouse motor cortex. Journal of Comparative Neurology, 524(4), 829-845. doi: 10.1002/cne.23875

Schoderboeck, L., Riad, S., Bokor, A. M., Wicky, H. E., Strauss, M., Bostina, M., Oswald, M. J., Empson, R. M., & Hughes, S. M. (2015). Chimeric rabies SADB19-VSVg-pseudotyped lentiviral vectors mediate long-range retrograde transduction from the mouse spinal cord. Gene Therapy, 22, 357-364. doi: 10.1038/gt.2015.3

Seeger-Armbruster, S., Bosch-Bouju, C., Little, S. T. C., Smither, R. A., Hughes, S. M., Hyland, B. I., & Parr-Brownlie, L. C. (2015). Patterned, but not tonic, optogenetic stimulation in motor thalamus improves reaching in acute drug-induced Parkinsonian rats. Journal of Neuroscience, 35(3), 1211-1216. doi: 10.1523/jneurosci.3277-14.2015

Parr-Brownlie, L. C., Bosch-Bouju, C., Schoderboeck, L., Sizemore, R. J., Abraham, W. C., & Hughes, S. M. (2015). Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms. Frontiers in Molecular Neuroscience, 8, 14. doi: 10.3389/fnmol.2015.00014

Neverman, N. J., Best, H. L., Hofmann, S. L., & Hughes, S. (2015). Experimental therapies in the neuronal ceroid lipofuscinoses. Biochimica et Biophysica Acta: Molecular Basis of Disease, 1852(10, Part B), 2292-2300. doi: 10.1016/j.bbadis.2015.04.026

Palmer, D. N., Neverman, N. J., Chen, J. Z., Chang, C.-T., Houweling, P. J., Barry, L. A., … Hughes, S. M., & Mitchell, N. L. (2015). Recent studies of ovine neuronal ceroid lipofuscinoses from BARN, the Batten Animal Research Network. Biochimica et Biophysica Acta: Molecular Basis of Disease, 1852(10, Part B), 2279-2286. doi: 10.1016/j.bbadis.2015.06.013

Hughes, S. M., Hope, K. M., Xu, J. B., Mitchell, N. L., & Palmer, D. N. (2014). Inhibition of storage pathology in prenatal CLN5-deficient sheep neural cultures by lentiviral gene therapy. Neurobiology of Disease, 62, 543-550. doi: 10.1016/j.nbd.2013.11.011

Tantirigama, M. L. S., Oswald, M. J., Duynstee, C., Hughes, S. M., & Empson, R. M. (2014). Expression of the developmental transcription factor Fezf2 identifies a distinct subpopulation of layer 5 intratelencephalic-projection neurons in mature mouse motor cortex. Journal of Neuroscience, 34(12), 4303-4308. doi: 10.1523/jneurosci.3111-13.2014

Oswald, M. J., Tantirigama, M. L. S., Sonntag, I., Hughes, S. M., & Empson, R. M. (2013). Diversity of layer 5 projection neurons in the mouse motor cortex. Frontiers in Cellular Neuroscience, 7, 174. doi: 10.3389/fncel.2013.00174

Jarvis, R. M., Hughes, S. M., & Ledgerwood, E. C. (2012). Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells. Free Radical Biology & Medicine, 53(7), 1522-1530. doi: 10.1016/j.freeradbiomed.2012.08.001

Dottori, M., Tay, C., & Hughes, S. M. (2011). Neural development in human embryonic stem cells—Applications of lentiviral vectors. Journal of Cellular Biochemistry, 112(8), 1955-1962. doi: 10.1002/jcb.23116

Linterman, K. S., Palmer, D. N., Kay, G. W., Barry, L. A., Mitchell, N. L., McFarlane, R. G., Black, M. A., … Hughes, S. M. (2011). Lentiviral-mediated gene transfer to the sheep brain: Implications for gene therapy in Batten disease. Human Gene Therapy, 22(8), 1011-1020. doi: 10.1089/hum.2011.026

Kells, A. P., Henry, R. A., Hughes, S. M., & Connor, B. (2007). Verification of functional AAV-mediated neurotrophic and anti-apoptotic factor expression. Journal of Neuroscience Methods, 161(2), 291-300. doi: 10.1016/j.jneumeth.2006.11.006

Chen, K., Hughes, S. M., & Connor, B. (2007). Neural progenitor cells derived from the adult rat subventricular zone: Characterization and transplantation. Cell Transplantation, 16(8), 799-810.

Gibbons, H. M., Hughes, S. M., Van Roon-Mom, W., Greenwood, J. M., Narayan, P. J., Teoh, H. H., … Dragunow, M. (2007). Cellular composition of human glial cultures from adult biopsy brain tissue. Journal of Neuroscience Methods, 166(1), 89-98. doi: 10.1016/j.jneumeth.2007.07.005

Gordon, R. J., Tattersfield, A. S., Vazey, E. M., Kells, A. P., McGregor, A. L., Hughes, S. M., & Connor, B. (2007). Temporal profile of subventricular zone progenitor cell migration following quinolinic acid–induced striatal cell loss. Neuroscience, 146(4), 1704-1718. doi: 10.1016/j.neuroscience.2007.03.011

Chen, K., Henry, R. A., Hughes, S. M., & Connor, B. (2007). Creating a neurogenic environment: The role of BDNF and FGF2. Molecular & Cellular Neuroscience, 36(1), 108-120. doi: 10.1016/j.mcn.2007.06.004

Henry, R. A., Hughes, S. M., & Connor, B. (2007). AAV-mediated delivery of BDNF augments neurogenesis in the normal and quinolinic acid-lesioned adult rat brain. European Journal of Neuroscience, 25(12), 3513-3525. doi: 10.1111/j.1460-9568.2007.05625.x

Vazey, E. M., Chen, K., Hughes, S. M., & Connor, B. (2006). Transplanted adult neural progenitor cells survive, differentiate and reduce motor function impairment in a rodent model of Huntington's disease. Experimental Neurology, 199(2), 384-396. doi: 10.1016/j.expneurol.2006.01.034

Hughes, S. M., Moroni-Rawson, P., Jolly, R. D., & Jordan, T. W. (2001). Sub-mitochondrial distribution and delayed proteolysis of subunit c of the H+-transporting ATP synthase in ovine ceroid-lipofuscinosis. Electrophoresis, 22, 1785-1794.

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