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Dr Natalie Connor-Robson
Cymrawd Ymchwil, Sefydliad Ymchwil Dementia
- Ar gael fel goruchwyliwr ôl-raddedig
Trosolwyg
Deall mecanweithiau moleciwlaidd clefyd Alzheimer
Mae gan glefyd Alzheimer gostau personol ac economaidd enfawr ac nid oes triniaethau effeithiol hyd yn hyn. Mae'n bwysig deall y mecanweithiau pathogenig cynharaf sy'n digwydd ar lefel gellog er mwyn dylunio opsiynau triniaeth gwell. Mae fy ymchwil yn canolbwyntio ar rôl y llwybr endocytig mewn niwroddirywiad ac ar ddeall sut mae newidiadau genetig cyffredin yn newid swyddogaeth gellog mewn Clefyd Alzheimer ysbeidiol. Rwy'n defnyddio niwronau a microglia sy'n deillio o iPSC i astudio hyn.
Nodau Ymchwil
- Astudio rôl camweithrediad endocytig mewn clefydau niwroddirywiol
- Adnabod mecanweithiau cellog pathogenig a achosir gan risg polygenig mewn Clefyd Alzheimer
- Ymchwilio i strategaethau therapiwtig newydd posibl
Cyhoeddiad
2024
- Ng, B. et al. 2024. Tau depletion in human neurons mitigates Aβ-driven toxicity. Molecular Psychiatry 29, pp. 2009-2020. (10.1038/s41380-024-02463-2)
- Brimblecombe, K. R. et al. 2024. Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's. European Journal of Neuroscience 59(6), pp. 1242-1259. (10.1111/ejn.16180)
- Kilfeather, P. et al. 2024. Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Cell Reports 43(3), article number: 113784. (10.1016/j.celrep.2024.113784)
- Maninger, J., Nowak, K., Goberdhan, S., O'Donoghue, R. and Connor-Robson, N. 2024. Cell type-specific functions of Alzheimer's disease endocytic risk genes. Philosophical Transactions of the Royal Society B: Biological Sciences 379(1899), article number: 20220378. (10.1098/rstb.2022.0378)
2023
- Williamson, M. G. et al. 2023. Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models. Human Molecular Genetics 32(18), pp. 2808-2821. (10.1093/hmg/ddad102)
2022
- Maguire, E., Connor-Robson, N., Shaw, B., O’Donoghue, R., Stöberl, N. and Hall-Roberts, H. 2022. Assaying microglia functions in vitro. Cells 11(21), article number: 3414. (10.3390/cells11213414)
2021
- Ninkina, N. et al. 2021. β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins. Journal of Biological Chemistry 297(6), article number: 101375. (10.1016/j.jbc.2021.101375)
- Threlfell, S. et al. 2021. Striatal dopamine transporter function is facilitated by converging biology of α-synuclein and cholesterol. Frontiers in Cellular Neuroscience 15, article number: 658244. (10.3389/fncel.2021.658244)
2020
- Roberts, B. M. et al. 2020. GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model. Nature Communications 11(1), article number: 4958. (10.1038/s41467-020-18247-5)
- Bengoa-Vergniory, N. et al. 2020. CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease. Nature Communications 11(1), article number: 4885. (10.1038/s41467-020-18689-x)
- Madureira, M., Connor-Robson, N. and Wade-Martins, R. 2020. LRRK2: Autophagy and Lysosomal Activity. Frontiers in Neuroscience 14, article number: 498. (10.3389/fnins.2020.00498)
- Simanaviciute, U. et al. 2020. Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits. Journal of Neuroscience Methods 331, article number: 108532. (10.1016/j.jneumeth.2019.108532)
2019
- Booth, H. D. et al. 2019. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiology of Disease 129, pp. 56-66. (10.1016/j.nbd.2019.05.006)
- Wallings, R., Connor-Robson, N. and Wade-Martins, R. 2019. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Human Molecular Genetics 28(16), pp. 2696–2710. (10.1093/hmg/ddz088)
- Connor-Robson, N. et al. 2019. An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2. Neurobiology of Disease 127, pp. 512-526. (10.1016/j.nbd.2019.04.005)
2018
- Vingill, S., Connor-Robson, N. and Wade-Martins, R. 2018. Are rodent models of Parkinson's disease behaving as they should?. Behavioural Brain Research 352, pp. 133-141. (10.1016/j.bbr.2017.10.021)
2016
- Connor-Robson, N., Peters, O., Millership, S., Ninkina, N. and Buchman, V. L. 2016. Combinational losses of synucleins reveal their differential requirements for compensating age-dependent alterations in motor behavior and dopamine metabolism. Neurobiology of Aging 46, pp. 107-112. (10.1016/j.neurobiolaging.2016.06.020)
- Telezhkin, V. et al. 2016. Forced cell-cycle exit and modulation of GABAA, CREB and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons. American Journal of Physiology - Cell Physiology, article number: ajpcell.00166.2015. (10.1152/ajpcell.00166.2015)
- Sloan, M. et al. 2016. LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function. Human Molecular Genetics 25(5), pp. 951-963. (10.1093/hmg/ddv628)
2015
- Ninkina, N., Connor-Robson, N., Ustyugov, A. A., Tarasova, T., Shelkovnikova, T. and Buchman, V. L. 2015. A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression. Scientific Reports 5, article number: 16615. (10.1038/srep16615)
2013
- Cooper-Knock, J. et al. 2013. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology 81(19), pp. 1719-1721. (10.1212/01.wnl.0000435295.41974.2e)
- Shelkovnikova, T., Robinson, H., Connor-Robson, N. and Buchman, V. L. 2013. Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle 12(19), pp. 3194-3202. (10.4161/cc.26241)
- Shelkovnikova, T. et al. 2013. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. Journal of Biological Chemistry 288(35), pp. 25266-25274. (10.1074/jbc.M113.492017)
- Connor-Robson, N. 2013. Synucleins in the midbrain dopaminergic system: the role in health and disease. PhD Thesis, Cardiff University.
- Peters, O. M. et al. 2013. Chronic administration of dimebon ameliorates pathology in Tau P301S transgenic mice. Journal of Alzheimer's Disease 33(4), pp. 1041-1049. (10.3233/JAD-2012-121732)
2012
- Ninkina, N., Peters, O. M., Connor-Robson, N., Lytkina, O., Sharfeddin, E. and Buchman, V. L. 2012. Contrasting effects of α-Synuclein and γ-Synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses. Journal of Biological Chemistry 287(53), pp. 44471-44477. (10.1074/jbc.M112.422402)
2011
- Anwar, S. et al. 2011. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. Journal of Neuroscience 31(20), pp. 7264-7274. (10.1523/JNEUROSCI.6194-10.2011)
Articles
- Ng, B. et al. 2024. Tau depletion in human neurons mitigates Aβ-driven toxicity. Molecular Psychiatry 29, pp. 2009-2020. (10.1038/s41380-024-02463-2)
- Brimblecombe, K. R. et al. 2024. Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's. European Journal of Neuroscience 59(6), pp. 1242-1259. (10.1111/ejn.16180)
- Kilfeather, P. et al. 2024. Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Cell Reports 43(3), article number: 113784. (10.1016/j.celrep.2024.113784)
- Maninger, J., Nowak, K., Goberdhan, S., O'Donoghue, R. and Connor-Robson, N. 2024. Cell type-specific functions of Alzheimer's disease endocytic risk genes. Philosophical Transactions of the Royal Society B: Biological Sciences 379(1899), article number: 20220378. (10.1098/rstb.2022.0378)
- Williamson, M. G. et al. 2023. Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models. Human Molecular Genetics 32(18), pp. 2808-2821. (10.1093/hmg/ddad102)
- Maguire, E., Connor-Robson, N., Shaw, B., O’Donoghue, R., Stöberl, N. and Hall-Roberts, H. 2022. Assaying microglia functions in vitro. Cells 11(21), article number: 3414. (10.3390/cells11213414)
- Ninkina, N. et al. 2021. β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins. Journal of Biological Chemistry 297(6), article number: 101375. (10.1016/j.jbc.2021.101375)
- Threlfell, S. et al. 2021. Striatal dopamine transporter function is facilitated by converging biology of α-synuclein and cholesterol. Frontiers in Cellular Neuroscience 15, article number: 658244. (10.3389/fncel.2021.658244)
- Roberts, B. M. et al. 2020. GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model. Nature Communications 11(1), article number: 4958. (10.1038/s41467-020-18247-5)
- Bengoa-Vergniory, N. et al. 2020. CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease. Nature Communications 11(1), article number: 4885. (10.1038/s41467-020-18689-x)
- Madureira, M., Connor-Robson, N. and Wade-Martins, R. 2020. LRRK2: Autophagy and Lysosomal Activity. Frontiers in Neuroscience 14, article number: 498. (10.3389/fnins.2020.00498)
- Simanaviciute, U. et al. 2020. Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits. Journal of Neuroscience Methods 331, article number: 108532. (10.1016/j.jneumeth.2019.108532)
- Booth, H. D. et al. 2019. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiology of Disease 129, pp. 56-66. (10.1016/j.nbd.2019.05.006)
- Wallings, R., Connor-Robson, N. and Wade-Martins, R. 2019. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Human Molecular Genetics 28(16), pp. 2696–2710. (10.1093/hmg/ddz088)
- Connor-Robson, N. et al. 2019. An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2. Neurobiology of Disease 127, pp. 512-526. (10.1016/j.nbd.2019.04.005)
- Vingill, S., Connor-Robson, N. and Wade-Martins, R. 2018. Are rodent models of Parkinson's disease behaving as they should?. Behavioural Brain Research 352, pp. 133-141. (10.1016/j.bbr.2017.10.021)
- Connor-Robson, N., Peters, O., Millership, S., Ninkina, N. and Buchman, V. L. 2016. Combinational losses of synucleins reveal their differential requirements for compensating age-dependent alterations in motor behavior and dopamine metabolism. Neurobiology of Aging 46, pp. 107-112. (10.1016/j.neurobiolaging.2016.06.020)
- Telezhkin, V. et al. 2016. Forced cell-cycle exit and modulation of GABAA, CREB and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons. American Journal of Physiology - Cell Physiology, article number: ajpcell.00166.2015. (10.1152/ajpcell.00166.2015)
- Sloan, M. et al. 2016. LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function. Human Molecular Genetics 25(5), pp. 951-963. (10.1093/hmg/ddv628)
- Ninkina, N., Connor-Robson, N., Ustyugov, A. A., Tarasova, T., Shelkovnikova, T. and Buchman, V. L. 2015. A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression. Scientific Reports 5, article number: 16615. (10.1038/srep16615)
- Cooper-Knock, J. et al. 2013. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology 81(19), pp. 1719-1721. (10.1212/01.wnl.0000435295.41974.2e)
- Shelkovnikova, T., Robinson, H., Connor-Robson, N. and Buchman, V. L. 2013. Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle 12(19), pp. 3194-3202. (10.4161/cc.26241)
- Shelkovnikova, T. et al. 2013. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. Journal of Biological Chemistry 288(35), pp. 25266-25274. (10.1074/jbc.M113.492017)
- Peters, O. M. et al. 2013. Chronic administration of dimebon ameliorates pathology in Tau P301S transgenic mice. Journal of Alzheimer's Disease 33(4), pp. 1041-1049. (10.3233/JAD-2012-121732)
- Ninkina, N., Peters, O. M., Connor-Robson, N., Lytkina, O., Sharfeddin, E. and Buchman, V. L. 2012. Contrasting effects of α-Synuclein and γ-Synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses. Journal of Biological Chemistry 287(53), pp. 44471-44477. (10.1074/jbc.M112.422402)
- Anwar, S. et al. 2011. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. Journal of Neuroscience 31(20), pp. 7264-7274. (10.1523/JNEUROSCI.6194-10.2011)
Thesis
- Connor-Robson, N. 2013. Synucleins in the midbrain dopaminergic system: the role in health and disease. PhD Thesis, Cardiff University.
- Booth, H. D. et al. 2019. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiology of Disease 129, pp. 56-66. (10.1016/j.nbd.2019.05.006)
- Cooper-Knock, J. et al. 2013. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology 81(19), pp. 1719-1721. (10.1212/01.wnl.0000435295.41974.2e)
- Shelkovnikova, T., Robinson, H., Connor-Robson, N. and Buchman, V. L. 2013. Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle 12(19), pp. 3194-3202. (10.4161/cc.26241)
- Shelkovnikova, T. et al. 2013. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. Journal of Biological Chemistry 288(35), pp. 25266-25274. (10.1074/jbc.M113.492017)
- Connor-Robson, N. 2013. Synucleins in the midbrain dopaminergic system: the role in health and disease. PhD Thesis, Cardiff University.
- Peters, O. M. et al. 2013. Chronic administration of dimebon ameliorates pathology in Tau P301S transgenic mice. Journal of Alzheimer's Disease 33(4), pp. 1041-1049. (10.3233/JAD-2012-121732)
- Ninkina, N., Peters, O. M., Connor-Robson, N., Lytkina, O., Sharfeddin, E. and Buchman, V. L. 2012. Contrasting effects of α-Synuclein and γ-Synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses. Journal of Biological Chemistry 287(53), pp. 44471-44477. (10.1074/jbc.M112.422402)
- Anwar, S. et al. 2011. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. Journal of Neuroscience 31(20), pp. 7264-7274. (10.1523/JNEUROSCI.6194-10.2011)
Bywgraffiad
Derbyniais fy BSc mewn Gwyddorau Biofeddygol o Brifysgol Caerdydd cyn cwblhau fy PhD ar rôl y teulu syniwclewin mewn iechyd a chlefydau. Yn 2014 ymunais â Chanolfan Clefyd Parkinson Rhydychen ym Mhrifysgol Rhydychen fel Cymrawd Datblygu Gyrfa yng ngrŵp yr Athro Richard Wade-Martins. Yn ystod y cyfnod hwn, gweithiais ar ddeall y digwyddiadau pathogenig cellog cynharaf i ddigwydd yng Nghlwy'r Parkinson's gan ddefnyddio modelau cnofilod a niwronau dopaminergig sy'n deillio o iPSC. Amlygodd fy ngwaith rolau helaeth treigladau LRRK2 yn y llwybrau endocytig ac awtophagic yn ogystal ag archwilio rôl GBA yn Parkinson's.
Yn 2021 cefais Gymrodoriaeth Ymchwil ARUK ac ymunais â'r UKDRI fel Arweinydd sy'n Dod i'r Amlwg.