![Gaynor Smith](https://profiles-cardiff.imgix.net/attachments/2602?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Dr Gaynor Smith
Senior Lecturer, Dementia Research Institute
- SmithGA@cardiff.ac.uk
- Hadyn Ellis Building, Room 1.03, Office F, Maindy Road, Cardiff, CF24 4HQ
- Available for postgraduate supervision
Overview
Molecular mechanisms of neurobiology, mitochondrial biology and neurodegenerative disease
Neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases are incurable and debilitating conditions that result in the progressive degeneration of different neuronal populations. Mitochondrial dysfunction, protein aggregation and altered glial responses are unifying features across these diseases and even manifest in prodromal stages. My laboratory is interested in understating the conserved molecular and cellular mechanisms underpinning these basic neurobiological processes, from Drosophila to humans.
Research Goals
- To discover new genes which control mitochondria maintenance in neurons using an unbiased in vivo genetic approach.
- To investigate how new genes discovered from GWAS approaches contribute to the pathological mechanisms of Alzheimer’s disease.
- To determine how changing redox homeostasis affects Alzheimer’s and Huntington’s disease progression.
Publication
2023
- Townsend, L. N. et al. 2023. Cdk12 maintains the integrity of adult axons by suppressing actin remodeling. Cell Death Discovery 9(1), article number: 348. (10.1038/s41420-023-01642-4)
- Rees, D. et al. 2023. Acyl-ghrelin attenuates neurochemical and motor deficits in the 6-OHDA model of Parkinson’s Disease. Cellular and Molecular Neurobiology 43, pp. 2377-2384. (10.1007/s10571-022-01282-9)
- Maddison, D. C., Malik, B., Amadio, L., Bis-Brewer, D. M., Züchner, S., Peters, O. M. and Smith, G. A. 2023. COPI-regulated mitochondria-ER contact site formation maintains axonal integrity. Cell Reports 42(8), article number: 112883. (10.1016/j.celrep.2023.112883)
- Smith, G., Sweeney, S. T., O’Kane, C. J. and Prokop, A. 2023. How neurons maintain their axons long-term: an integrated view of axon biology and pathology. Frontiers in Neuroscience 17, article number: 1236815. (10.3389/fnins.2023.1236815)
- Maddison, D., Mattedi, F., Vagnoni, A. and Smith, G. A. 2023. Clonal imaging of mitochondria in the dissected fly wing. Cold Spring Harbor Protocol 2023(2), article number: 108051. (10.1101/pdb.prot108051)
- Maddison, D., Mattedi, F., Vagnoni, A. and Smith, G. A. 2023. Analysis of mitochondrial dynamics in adult drosophila axons. Cold Spring Harbor Protocol 2023(2), article number: 107819. (10.1101/pdb.top107819)
- Mattedi, F., Maddison, D., Smith, G. A. and Vagnoni, A. 2023. Live imaging of mitochondria in the intact fly wing. Cold Spring Harbor Protocol 2023(2), article number: 108052. (10.1101/pdb.prot108052)
2021
- Peters, O. M. et al. 2021. Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease. Neurobiology of Disease 155, article number: 105368. (10.1016/j.nbd.2021.105368)
- Lin, T. et al. 2021. TSG101 negatively regulates mitochondrial biogenesis in axons. Proceedings of the National Academy of Sciences 118(20), article number: e2018770118. (10.1073/pnas.2018770118)
2020
- Precious, S. V. et al. 2020. Dopaminergic progenitors derived from epiblast stem cells function similarly to primary VM-derived progenitors when transplanted into a Parkinson’s disease model. Frontiers in Neuroscience 14, article number: 312. (10.3389/fnins.2020.00312)
2019
- Malik, B. R., Maddison, D. C., Smith, G. A. and Peters, O. M. 2019. Autophagic and endo-lysosomal dysfunction in neurodegenerative disease. Molecular Brain 12(1), article number: 100. (10.1186/s13041-019-0504-x)
- Smith, G. A. et al. 2019. Glutathione-S-transferase regulates mitochondrial populations in axons through increased glutathione oxidation. Neuron 103(1), pp. 52-65.e6. (10.1016/j.neuron.2019.04.017)
2017
- Breger, L. S., Kienle, K., Smith, G. A., Dunnett, S. B. and Lane, E. L. 2017. Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease. Brain, Behavior, and Immunity 61, pp. 155-164. (10.1016/j.bbi.2016.11.014)
2016
- Smith, G. A., Jansson, J., Rocha, E. M., Osborn, T., Hallett, P. J. and Isacson, O. 2016. Fibroblast biomarkers of sporadic Parkinson's Disease and LRRK2 kinase inhibition. Molecular Neurobiology 53(8), pp. 5161-5177. (10.1007/s12035-015-9435-4)
- Lewis, E. A. and Smith, G. A. 2016. Using Drosophila models of Huntington's disease as a translatable tool. Journal of Neuroscience Methods 265, pp. 89-98. (10.1016/j.jneumeth.2015.07.026)
2015
- Rocha, E. M. et al. 2015. Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons. Neurobiology of Disease 82, pp. 495-503. (10.1016/j.nbd.2015.09.009)
- Rocha, E. M. et al. 2015. Sustained systemic glucocerebrosidase inhibition induces brain α-Synuclein aggregation, microglia and complement C1q activation in mice. Antioxidants and Redox Signaling 23(6), pp. 550-564. (10.1089/ars.2015.6307)
- Rocha, E. M., Smith, G. A., Park, E., Cao, H., Brown, E., Hallett, P. and Isacson, O. 2015. Progressive decline of glucocerebrosidase in aging and Parkinson's disease. Annals of Clinical and Translational Neurology 2(4), pp. 433-438. (10.1002/acn3.177)
- Smith, G. A. et al. 2015. A nurr1 agonist causes neuroprotection in a Parkinson's Disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C). PLoS ONE 10(3), article number: e0121072. (10.1371/journal.pone.0121072)
- Hallett, P. et al. 2015. Successful function of Autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell 16(3), pp. 269-274. (10.1016/j.stem.2015.01.018)
2014
- McLean, J. R. et al. 2014. ALS-associated peripherin spliced transcripts form distinct protein inclusions that are neuroprotective against oxidative stress. Experimental Neurology 261, pp. 217-229. (10.1016/j.expneurol.2014.05.024)
- Smith, G. A., Rocha, E. M., McLean, J. R., Hayes, M. A., Izen, S. C., Isacson, O. and Hallett, P. J. 2014. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington's disease. Human Molecular Genetics 23(17), pp. 4510-4527. (10.1093/hmg/ddu166)
- McLean, J. R., Smith, G. A., Rocha, E. M., Hayes, M. A., Beagan, J. A., Hallett, P. J. and Isacson, O. 2014. Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection. Neuroscience Letters. 576, pp. 73-78. (10.1016/j.neulet.2014.05.044)
- Davies, S. E. et al. 2014. Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease. Neurobiology of Disease 64, pp. 79-87. (10.1016/j.nbd.2013.12.011)
2013
- Smith, G. A. and Snyder, E. Y. 2013. Two cells are better than one: optimizing stem cell survival by co-grafting “helper” cells that offer regulated trophic support. Experimental Neurology 247, pp. 751-754. (10.1016/j.expneurol.2013.07.003)
- Peters, O. M. et al. 2013. Chronic administration of dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice. Journal of Alzheimer's Disease 36(3), pp. 589-596. (10.3233/JAD-130071)
- Heuer, A., Smith, G. A. and Dunnett, S. B. 2013. Comparison of 6-hydroxydopamine lesions of the substantia nigra and the medial forebrain bundle on a lateralised choice reaction time task in mice. European Journal of Neuroscience 37(2), pp. 294-302. (10.1111/ejn.12036)
- Sundberg, M. et al. 2013. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells 31(8), pp. 1548-152. (10.1002/stem.1415)
2012
- Smith, G. A., Isacson, O. and Dunnett, S. B. 2012. The search for genetic mouse models of prodromal Parkinson's disease. Experimental Neurology 237(2), pp. 267-273. (10.1016/j.expneurol.2012.06.035)
- Smith, G. A., Breger, L. S., Lane, E. L. and Dunnett, S. B. 2012. Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats. Neuropharmacology 63(5), pp. 818-828. (10.1016/j.neuropharm.2012.06.011)
- Smith, G. A., Dunnett, S. B. and Lane, E. L. 2012. Amphetamine-induced rotation in the transplanted hemi-parkinsonian rat - Response to pharmacological modulation. Behavioural Brain Research 232(2), pp. 411-415. (10.1016/j.bbr.2012.04.003)
- Smith, G. A., Heuer, A., Dunnett, S. B. and Lane, E. L. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice II: Predicting L-DOPA-induced dyskinesia. Behavioural Brain Research 226(1), pp. 281-292. (10.1016/j.bbr.2011.09.025)
- Heuer, A., Smith, G. A., Lelos, M. J., Lane, E. L. and Dunnett, S. B. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: Motor impairments identify extent of dopamine depletion at three different lesion sites. Behavioural Brain Research 228(1), pp. 30-43. (10.1016/j.bbr.2011.11.027)
- Smith, G. A. et al. 2012. L-dopa and graft-induced dyskinesia in the 6-OHDA-lesioned mouse [Abstract]. Cell Transplantation 21(4), pp. 792-792.
- Smith, G. A., Heuer, A., Klein, A., Vinh, N., Dunnett, S. B. and Lane, E. 2012. Amphetamine-induced dyskinesia in the transplanted hemi-Parkinsonian mouse. Journal of Parkinson's Disease 2, pp. 107-113. (10.3233/JPD-2012-12102)
2011
- Torres, E. M., Lane, E. L., Heuer, A., Smith, G. A., Murphy, E. M. and Dunnett, S. B. 2011. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates. Journal of Neuroscience Methods 200(1), pp. 29-35. (10.1016/j.jneumeth.2011.06.012)
- Lane, E. L., Daly, C. S., Smith, G. A. and Dunnett, S. B. 2011. Context-driven changes in 1-DOPA-induced behaviours in the 6-OHDA lesioned rat. Neurobiology of Disease 42(1), pp. 99-107. (10.1016/j.nbd.2011.01.010)
- Smith, G. A., Lane, E. L. and Dunnett, S. B. 2011. Graft-Induced Dyskinesia in Transplanted Hemiparkinsonian Mice and Rats: A Pharmacological Manipulation [Abstract]. Cell Transplantation 20(4), pp. 585-585.
- Smith, G. A., Breger, L. S., Dunnett, S. B. and Lane, E. L. 2011. Developments in Graft-Induced Dyskinesia [Abstract]. Cell Transplantation 20(4), pp. 584-585.
- Smith, G. 2011. Optimisation and mechanistic insights of dyskinesia in rodent models of Parkinson’s disease. PhD Thesis, Cardiff University.
2010
- Lane, E. L. and Smith, G. A. 2010. Understanding graft-induced dyskinesia. Regenerative Medicine 5(5), pp. 787-797. (10.2217/rme.10.42)
Articles
- Townsend, L. N. et al. 2023. Cdk12 maintains the integrity of adult axons by suppressing actin remodeling. Cell Death Discovery 9(1), article number: 348. (10.1038/s41420-023-01642-4)
- Rees, D. et al. 2023. Acyl-ghrelin attenuates neurochemical and motor deficits in the 6-OHDA model of Parkinson’s Disease. Cellular and Molecular Neurobiology 43, pp. 2377-2384. (10.1007/s10571-022-01282-9)
- Maddison, D. C., Malik, B., Amadio, L., Bis-Brewer, D. M., Züchner, S., Peters, O. M. and Smith, G. A. 2023. COPI-regulated mitochondria-ER contact site formation maintains axonal integrity. Cell Reports 42(8), article number: 112883. (10.1016/j.celrep.2023.112883)
- Smith, G., Sweeney, S. T., O’Kane, C. J. and Prokop, A. 2023. How neurons maintain their axons long-term: an integrated view of axon biology and pathology. Frontiers in Neuroscience 17, article number: 1236815. (10.3389/fnins.2023.1236815)
- Maddison, D., Mattedi, F., Vagnoni, A. and Smith, G. A. 2023. Clonal imaging of mitochondria in the dissected fly wing. Cold Spring Harbor Protocol 2023(2), article number: 108051. (10.1101/pdb.prot108051)
- Maddison, D., Mattedi, F., Vagnoni, A. and Smith, G. A. 2023. Analysis of mitochondrial dynamics in adult drosophila axons. Cold Spring Harbor Protocol 2023(2), article number: 107819. (10.1101/pdb.top107819)
- Mattedi, F., Maddison, D., Smith, G. A. and Vagnoni, A. 2023. Live imaging of mitochondria in the intact fly wing. Cold Spring Harbor Protocol 2023(2), article number: 108052. (10.1101/pdb.prot108052)
- Peters, O. M. et al. 2021. Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease. Neurobiology of Disease 155, article number: 105368. (10.1016/j.nbd.2021.105368)
- Lin, T. et al. 2021. TSG101 negatively regulates mitochondrial biogenesis in axons. Proceedings of the National Academy of Sciences 118(20), article number: e2018770118. (10.1073/pnas.2018770118)
- Precious, S. V. et al. 2020. Dopaminergic progenitors derived from epiblast stem cells function similarly to primary VM-derived progenitors when transplanted into a Parkinson’s disease model. Frontiers in Neuroscience 14, article number: 312. (10.3389/fnins.2020.00312)
- Malik, B. R., Maddison, D. C., Smith, G. A. and Peters, O. M. 2019. Autophagic and endo-lysosomal dysfunction in neurodegenerative disease. Molecular Brain 12(1), article number: 100. (10.1186/s13041-019-0504-x)
- Smith, G. A. et al. 2019. Glutathione-S-transferase regulates mitochondrial populations in axons through increased glutathione oxidation. Neuron 103(1), pp. 52-65.e6. (10.1016/j.neuron.2019.04.017)
- Breger, L. S., Kienle, K., Smith, G. A., Dunnett, S. B. and Lane, E. L. 2017. Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease. Brain, Behavior, and Immunity 61, pp. 155-164. (10.1016/j.bbi.2016.11.014)
- Smith, G. A., Jansson, J., Rocha, E. M., Osborn, T., Hallett, P. J. and Isacson, O. 2016. Fibroblast biomarkers of sporadic Parkinson's Disease and LRRK2 kinase inhibition. Molecular Neurobiology 53(8), pp. 5161-5177. (10.1007/s12035-015-9435-4)
- Lewis, E. A. and Smith, G. A. 2016. Using Drosophila models of Huntington's disease as a translatable tool. Journal of Neuroscience Methods 265, pp. 89-98. (10.1016/j.jneumeth.2015.07.026)
- Rocha, E. M. et al. 2015. Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons. Neurobiology of Disease 82, pp. 495-503. (10.1016/j.nbd.2015.09.009)
- Rocha, E. M. et al. 2015. Sustained systemic glucocerebrosidase inhibition induces brain α-Synuclein aggregation, microglia and complement C1q activation in mice. Antioxidants and Redox Signaling 23(6), pp. 550-564. (10.1089/ars.2015.6307)
- Rocha, E. M., Smith, G. A., Park, E., Cao, H., Brown, E., Hallett, P. and Isacson, O. 2015. Progressive decline of glucocerebrosidase in aging and Parkinson's disease. Annals of Clinical and Translational Neurology 2(4), pp. 433-438. (10.1002/acn3.177)
- Smith, G. A. et al. 2015. A nurr1 agonist causes neuroprotection in a Parkinson's Disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C). PLoS ONE 10(3), article number: e0121072. (10.1371/journal.pone.0121072)
- Hallett, P. et al. 2015. Successful function of Autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell 16(3), pp. 269-274. (10.1016/j.stem.2015.01.018)
- McLean, J. R. et al. 2014. ALS-associated peripherin spliced transcripts form distinct protein inclusions that are neuroprotective against oxidative stress. Experimental Neurology 261, pp. 217-229. (10.1016/j.expneurol.2014.05.024)
- Smith, G. A., Rocha, E. M., McLean, J. R., Hayes, M. A., Izen, S. C., Isacson, O. and Hallett, P. J. 2014. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington's disease. Human Molecular Genetics 23(17), pp. 4510-4527. (10.1093/hmg/ddu166)
- McLean, J. R., Smith, G. A., Rocha, E. M., Hayes, M. A., Beagan, J. A., Hallett, P. J. and Isacson, O. 2014. Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection. Neuroscience Letters. 576, pp. 73-78. (10.1016/j.neulet.2014.05.044)
- Davies, S. E. et al. 2014. Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease. Neurobiology of Disease 64, pp. 79-87. (10.1016/j.nbd.2013.12.011)
- Smith, G. A. and Snyder, E. Y. 2013. Two cells are better than one: optimizing stem cell survival by co-grafting “helper” cells that offer regulated trophic support. Experimental Neurology 247, pp. 751-754. (10.1016/j.expneurol.2013.07.003)
- Peters, O. M. et al. 2013. Chronic administration of dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice. Journal of Alzheimer's Disease 36(3), pp. 589-596. (10.3233/JAD-130071)
- Heuer, A., Smith, G. A. and Dunnett, S. B. 2013. Comparison of 6-hydroxydopamine lesions of the substantia nigra and the medial forebrain bundle on a lateralised choice reaction time task in mice. European Journal of Neuroscience 37(2), pp. 294-302. (10.1111/ejn.12036)
- Sundberg, M. et al. 2013. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells 31(8), pp. 1548-152. (10.1002/stem.1415)
- Smith, G. A., Isacson, O. and Dunnett, S. B. 2012. The search for genetic mouse models of prodromal Parkinson's disease. Experimental Neurology 237(2), pp. 267-273. (10.1016/j.expneurol.2012.06.035)
- Smith, G. A., Breger, L. S., Lane, E. L. and Dunnett, S. B. 2012. Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats. Neuropharmacology 63(5), pp. 818-828. (10.1016/j.neuropharm.2012.06.011)
- Smith, G. A., Dunnett, S. B. and Lane, E. L. 2012. Amphetamine-induced rotation in the transplanted hemi-parkinsonian rat - Response to pharmacological modulation. Behavioural Brain Research 232(2), pp. 411-415. (10.1016/j.bbr.2012.04.003)
- Smith, G. A., Heuer, A., Dunnett, S. B. and Lane, E. L. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice II: Predicting L-DOPA-induced dyskinesia. Behavioural Brain Research 226(1), pp. 281-292. (10.1016/j.bbr.2011.09.025)
- Heuer, A., Smith, G. A., Lelos, M. J., Lane, E. L. and Dunnett, S. B. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: Motor impairments identify extent of dopamine depletion at three different lesion sites. Behavioural Brain Research 228(1), pp. 30-43. (10.1016/j.bbr.2011.11.027)
- Smith, G. A. et al. 2012. L-dopa and graft-induced dyskinesia in the 6-OHDA-lesioned mouse [Abstract]. Cell Transplantation 21(4), pp. 792-792.
- Smith, G. A., Heuer, A., Klein, A., Vinh, N., Dunnett, S. B. and Lane, E. 2012. Amphetamine-induced dyskinesia in the transplanted hemi-Parkinsonian mouse. Journal of Parkinson's Disease 2, pp. 107-113. (10.3233/JPD-2012-12102)
- Torres, E. M., Lane, E. L., Heuer, A., Smith, G. A., Murphy, E. M. and Dunnett, S. B. 2011. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates. Journal of Neuroscience Methods 200(1), pp. 29-35. (10.1016/j.jneumeth.2011.06.012)
- Lane, E. L., Daly, C. S., Smith, G. A. and Dunnett, S. B. 2011. Context-driven changes in 1-DOPA-induced behaviours in the 6-OHDA lesioned rat. Neurobiology of Disease 42(1), pp. 99-107. (10.1016/j.nbd.2011.01.010)
- Smith, G. A., Lane, E. L. and Dunnett, S. B. 2011. Graft-Induced Dyskinesia in Transplanted Hemiparkinsonian Mice and Rats: A Pharmacological Manipulation [Abstract]. Cell Transplantation 20(4), pp. 585-585.
- Smith, G. A., Breger, L. S., Dunnett, S. B. and Lane, E. L. 2011. Developments in Graft-Induced Dyskinesia [Abstract]. Cell Transplantation 20(4), pp. 584-585.
- Lane, E. L. and Smith, G. A. 2010. Understanding graft-induced dyskinesia. Regenerative Medicine 5(5), pp. 787-797. (10.2217/rme.10.42)
Thesis
- Smith, G. 2011. Optimisation and mechanistic insights of dyskinesia in rodent models of Parkinson’s disease. PhD Thesis, Cardiff University.
- Breger, L. S., Kienle, K., Smith, G. A., Dunnett, S. B. and Lane, E. L. 2017. Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease. Brain, Behavior, and Immunity 61, pp. 155-164. (10.1016/j.bbi.2016.11.014)
- Peters, O. M. et al. 2013. Chronic administration of dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice. Journal of Alzheimer's Disease 36(3), pp. 589-596. (10.3233/JAD-130071)
- Heuer, A., Smith, G. A. and Dunnett, S. B. 2013. Comparison of 6-hydroxydopamine lesions of the substantia nigra and the medial forebrain bundle on a lateralised choice reaction time task in mice. European Journal of Neuroscience 37(2), pp. 294-302. (10.1111/ejn.12036)
- Smith, G. A., Isacson, O. and Dunnett, S. B. 2012. The search for genetic mouse models of prodromal Parkinson's disease. Experimental Neurology 237(2), pp. 267-273. (10.1016/j.expneurol.2012.06.035)
- Smith, G. A., Breger, L. S., Lane, E. L. and Dunnett, S. B. 2012. Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats. Neuropharmacology 63(5), pp. 818-828. (10.1016/j.neuropharm.2012.06.011)
- Smith, G. A., Dunnett, S. B. and Lane, E. L. 2012. Amphetamine-induced rotation in the transplanted hemi-parkinsonian rat - Response to pharmacological modulation. Behavioural Brain Research 232(2), pp. 411-415. (10.1016/j.bbr.2012.04.003)
- Smith, G. A., Heuer, A., Dunnett, S. B. and Lane, E. L. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice II: Predicting L-DOPA-induced dyskinesia. Behavioural Brain Research 226(1), pp. 281-292. (10.1016/j.bbr.2011.09.025)
- Heuer, A., Smith, G. A., Lelos, M. J., Lane, E. L. and Dunnett, S. B. 2012. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: Motor impairments identify extent of dopamine depletion at three different lesion sites. Behavioural Brain Research 228(1), pp. 30-43. (10.1016/j.bbr.2011.11.027)
- Smith, G. A. et al. 2012. L-dopa and graft-induced dyskinesia in the 6-OHDA-lesioned mouse [Abstract]. Cell Transplantation 21(4), pp. 792-792.
- Torres, E. M., Lane, E. L., Heuer, A., Smith, G. A., Murphy, E. M. and Dunnett, S. B. 2011. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates. Journal of Neuroscience Methods 200(1), pp. 29-35. (10.1016/j.jneumeth.2011.06.012)
- Lane, E. L., Daly, C. S., Smith, G. A. and Dunnett, S. B. 2011. Context-driven changes in 1-DOPA-induced behaviours in the 6-OHDA lesioned rat. Neurobiology of Disease 42(1), pp. 99-107. (10.1016/j.nbd.2011.01.010)
- Smith, G. A., Lane, E. L. and Dunnett, S. B. 2011. Graft-Induced Dyskinesia in Transplanted Hemiparkinsonian Mice and Rats: A Pharmacological Manipulation [Abstract]. Cell Transplantation 20(4), pp. 585-585.
- Smith, G. A., Breger, L. S., Dunnett, S. B. and Lane, E. L. 2011. Developments in Graft-Induced Dyskinesia [Abstract]. Cell Transplantation 20(4), pp. 584-585.
- Smith, G. 2011. Optimisation and mechanistic insights of dyskinesia in rodent models of Parkinson’s disease. PhD Thesis, Cardiff University.
- Lane, E. L. and Smith, G. A. 2010. Understanding graft-induced dyskinesia. Regenerative Medicine 5(5), pp. 787-797. (10.2217/rme.10.42)
Research
Research Goals
To discover new genes which control mitochondria maintenance in the axons of neurons using an unbiased in vivo genetic approach.
We know relatively little about the basic biology of mitochondrial biogenesis, morphological changes, transport, or function in axons in vivo, yet mitochondrial abnormalities in the terminals have been strongly linked to the etiology of several neurodegenerative disorders.
Neuronal health is maintained by the balance between constant degradation of damaged mitochondria through mitophagy and biogenesis. These pathways are highly conserved from humans to invertebrates. Mitophagy requires the coordinated action of PINK1 and Parkin and the genetic interaction of these two molecules was discovered using Drosophila (Park et al., 2006).
Work from Drosophila also revealed that two key proteins, Miro and Milton, are needed to transport mitochondria and orchestrate their disengagement from the cytoskeleton in areas of high Ca2+ to enhance buffering (reviewed by Tang, 2016).
Mitochondria are also highly dynamic in the axon and undergo constant fusion and fission to share or avoid mixing mtDNA and proteins depending on the status of the neuron. OPA-1, Marf, Drp1 and Fis1 have so far been discovered as the main regulators of fission/ fusion balance.
My lab performs unbiased genetic screening in fruit flies to discover new mitochondrial regulators in axons, which may be applicable to neurodegenerative disease and characterize their function. Other interests include understanding how mitochondria “communicate” with other organelles such as peroxisomes and endoplasmic reticulum to drive metabolic processes.
To investigate how new genes discovered from GWAS approaches contribute to the pathological mechanisms of Alzheimer’s disease.
The number of people living with dementia in the UK is forecast to increase to approximately 1 million by 2025 and over 2 million by 2051 (https://www.alzheimers.org.uk/) and there is currently no treatment that can help slow down disease progression.
Key pathological features of the disease are dysregulated neuroimmune interactions, metabolic changes, transcriptional changes and the build up of amyloid plaques. Insights into the genetic origins of Alzheimer’s disease have been made through Genome Wide Association Studies (GWAS), in which Cardiff University has played a major role, spearheaded by Prof. Julie Williams.
My lab, in collaboration with Dr Owen Peters and members of the Dementia Research Institute (DRI) will focus on understanding the genetics of these key pathological processes that contribute to Alzheimer’s disease using Drosophila and information gathered through GWAS.
To determine how changing redox homeostasis affects Alzheimer’s and Huntington’s disease progression.
Free radicals generated by mitochondria can become harmful to neurons unless they are quenched by antioxidants.
My lab is interested in understating how molecules involved in redox status contribute to neurodegeneration, with specific focus on peroxidases, transferases and reductases that reside either within the mitochondria or axoplasm.
Teaching
MBBCh - SSC - Year 1 Tutor
MBBCh- ME2100 - Case Based Learning facilitator
MBBCh - Personal Tutor
ME3048 Medical pharmacology - Supervisor
BI3001 Final year project - Supervisor
BI4001 Advanced research project - Supervisor
PTY - Supervisor
Biography
I obtained my BSc in Physiology from Cardiff University and remained there to completed my PhD in the laboratory of Prof. Stephan Dunnett where I focused on understanding how treatment strategies such as cell transplantation and L-DOPA therapy effected the phenotypic outcome of Parkinson’s models.
I began my post-doctoral training at Harvard Medical School in the laboratory of Prof. Ole Isacson where I characterized the histopathological and behavioural deficits in the Q175 mouse model of Huntington’s disease, and used gene therapy stratagies and small molecule administration to mitigate phenotypes in rodent models of Parkinson’s disease. I further studied several mitochondrial phenotypes in Parkinson’s patient and control tissue samples that were exposed to mitochondrial specific toxins. This drove differential changes in mitochondrial morphology, LRRK2 phosphorylation, reactive oxygen species generation, mitochondrial membrane potential and mitophagy levels.
During my second post-doctoral position in the laboratory of Prof. Marc Freeman, first based at the University of Massachusetts then moving to Oregon Health and Science University I continued to study mitochondria in Drosophila and screened for new modifiers of mitochondrial dynamics in neurons.
My own research group at Cardiff University will continue to study mitochondrial dynamics in neurons and investigate genetic modifiers of Alzheimer’s disease and Huntington’s disease.
Supervisions
I am interested in supervising PhD students in the areas of:
- Neuroscience
- Neurodegenerative disease
- Mitochondrial biology
- Axon biology
Engagement
I am a trained as a STEM ambassador. I am involved with 'Brain Games' events held at Cardiff Museum and also contributed to patient and career events run by local charities both within the University and externally. I also contribute to Pint of Science, with my lastest lecture centered on how we use fruit flies in research "Me, Myself and Fly". I also also take part in the In2 Science mentor scheme, which offers small group sessions and a placement day for Year 12 high school students from disadvantaged backgrounds.
Research themes
Specialisms
- Mitochondria
- Drosophila
- Alzheimer's disease
- neuron