![Vladimir Buchman](https://profiles-cardiff.imgix.net/attachments/944?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Yr Athro Vladimir Buchman
Athro Emeritws
Ysgol y Biowyddorau
Trosolwyg
Trosolwg ymchwil
Prif nod ein hymchwil yw deall mecanweithiau moleciwlaidd sy'n ymwneud â phathogenau clefydau niwroddirywiol a metabolig dynol penodol. Ar hyn o bryd rydym yn canolbwyntio ar astudiaethau o swyddogaeth arferol sawl teulu protein a chamweithrediad aelodau o'r teulu sy'n gysylltiedig â phatholegau dynol. Defnyddir gwahanol ddulliau arbrofol sy'n amrywio o ryngweithiadau macromolecule in vitro i gynhyrchu a nodweddu modelau anifeiliaid yn ffenotypical yn yr astudiaethau hyn.
Cyhoeddiad
2024
- Sennett, C. et al. 2024. α-synuclein deletion impairs platelet function: A role for SNARE complex assembly. Cells 13(24), article number: 2089. (10.3390/cells13242089)
- Jensen, N. M. et al. 2024. MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity. npj Parkinson's Disease 10, article number: 227. (10.1038/s41531-024-00841-9)
- Aubrey, L. D. et al. 2024. Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid. Proceedings of the National Academy of Sciences 121(2), article number: e2309700120. (10.1073/pnas.2309700120)
2022
- Chaprov, K., Sukhanova, I., Grineva, A. and Buchman, V. 2022. Beta-Synuclein protein function in behavioral impairment of triple knockout mouse model. Neuroscience Applied, article number: 100353. (10.1016/j.nsa.2022.100353)
- Vorobyov, V., Deev, A., Sukhanova, I., Morozova, O., Oganesyan, Z., Chaprov, K. and Buchman, V. L. 2022. Loss of the synuclein family members differentially affectsbBaseline- and apomorphine-associated EEG determinants in single-, double- and triple-knockout mice. Biomedicines 10(12), article number: 3128. (10.3390/biomedicines10123128)
- Ulamec, S. M. et al. 2022. Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein. Nature Communications 13(1), article number: 4986. (10.1038/s41467-022-32687-1)
- Carnazza, K. E. et al. 2022. Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins. Cell Reports 39(2), article number: 110675. (10.1016/j.celrep.2022.110675)
- An, H. et al. 2022. ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity. Neurobiology of Disease 162, article number: 105585. (10.1016/j.nbd.2021.105585)
2021
- Chaprov, K. D., Lysikova, E. A., Teterina, E. V. and Buchman, V. L. 2021. Kinetics of alpha-synuclein depletion in three brain regions following conditional pan-neuronal inactivation of the encoding gene (Snca) by tamoxifen-induced Cre-recombination in adult mice. Transgenic Research 30, pp. 867-873. (10.1007/s11248-021-00286-3)
- 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)
- Upcott, M., Chaprov, K. D. and Buchman, V. 2021. Towards disease-modifying therapy of alpha-synucleinopathies: new molecules and new approaches came into the lime-light. Molecules 26(23), article number: 7351. (10.3390/molecules26237351)
- Kukharsky, M. S., Skvortsova, V. I., Bachurin, S. O. and Buchman, V. L. 2021. In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches. Medicinal Research Reviews 41(5), pp. 2804-2822. (10.1002/med.21725)
- Chaprov, K. et al. 2021. A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice. CNS Neuroscience and Therapeutics 27(7), pp. 765-775. (10.1111/cns.13637)
- Guschina, I. A., Ninkina, N., Roman, A., Pokrovskiy, M. V. and Buchman, V. L. 2021. Triple-knockout, synuclein-free mice display compromised lipid pattern. Molecules 26(11), article number: 3078. (10.3390/molecules26113078)
2020
- Hosford, P. S., Ninkina, N., Buchman, V. L., Smith, J. C., Marina, N. and SheikhBahaei, S. 2020. Synuclein deficiency results in age-related respiratory and cardiovascular dysfunctions in mice. Brain Sciences 10(9), article number: 583. (10.3390/brainsci10090583)
- Ninkina, N. et al. 2020. Alterations in the nigrostriatal system following conditional inactivation of α-synuclein in neurons of adult and aging mice. Neurobiology of Aging 91, pp. 76-87. (10.1016/j.neurobiolaging.2020.02.026)
- Lysikova, E. A. et al. 2020. Low level of expression of C-terminally truncated human FUS causes extensive changes in the spinal cord transcriptome of asymptomatic transgenic mice. Neurochemical Research 45, pp. 1168-1179. (10.1007/s11064-020-02999-z)
- Kukharsky, M. S. et al. 2020. Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice. Translational Psychiatry 10, article number: 171. (10.1038/s41398-020-0854-2)
- An, H., Rabesahala de Meritens, C., Buchman, V. L. and Shelkovnikova, T. A. 2020. Frameshift peptides alter the properties of truncated FUS proteins in ALS-FUS. Molecular Brain 13, article number: 77. (10.1186/s13041-020-00618-0)
- Goloborshcheva, V. V., Chaprov, K. D., Teterina, E. V., Ovchinnikov, R. and Buchman, V. L. 2020. Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein. Molecular Brain 13(1), article number: 75. (10.1186/s13041-020-00613-5)
2019
- Shelkovnikova, T. A., An, H., Skelt, L., Tregoning, J. S., Humphreys, I. R. and Buchman, V. L. 2019. Antiviral immune response as a trigger of FUS proteinopathy in amyotrophic lateral sclerosis. Cell Reports 29(13), pp. 4496-4508.e4. (10.1016/j.celrep.2019.11.094)
- Lysikova, E. A. et al. 2019. Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration.. Genes, Brain and Behavior 18(8), article number: e12607. (10.1111/gbb.12607)
- Ninkina, N., Kukharsky, M. S., Hewitt, M. V., Lysikova, E. A., Skuratovska, L. N., Deykin, A. V. and Buchman, V. 2019. Stem cells in human breast milk. Human Cell 32(3), pp. 223-230. (10.1007/s13577-019-00251-7)
- Egorova, T. V. et al. 2019. CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD gene. Disease Models and Mechanisms 12(4), pp. -., article number: dmm037655. (10.1242/dmm.037655)
- An, H. et al. 2019. ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles. Acta Neuropathologica Communications 7, article number: 7. (10.1186/s40478-019-0658-x)
2018
- Skvortsova, V., Bachurin, S., Ustyugov, A., Kukharsky, M., Deikin, A., Buchman, V. L. and Ninkina, N. 2018. Gamma-carbolines derivatives as promising agents for the development of pathogenic therapy for proteinopathy. Acta Naturae 10(4), pp. 59-62.
- Shelkovnikova, T. A. et al. 2018. Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis. Molecular Neurodegeneration 13, article number: 30. (10.1186/s13024-018-0263-7)
2017
- Shelkovnikova, T. et al. 2017. Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly. Cell Death and Disease 8, article number: e2788. (10.1038/cddis.2017.199)
- Roman, A. Y., Limorenko, G., Ustyugov, A. A., Tarasova, T., Lysikova, E. A., Buchman, V. L. and Ninkina, N. 2017. Generation of mouse lines with conditionally or constitutively inactivated Snca gene and Rosa26-stop-lacZ reporter located in cis on the mouse chromosome 6. Transgenic Research 26(2), pp. 301-307. (10.1007/s11248-016-9995-8)
- Dimasi, P., Quintiero, A., Shelkovnikova, T. and Buchman, V. L. 2017. Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose. Scientific Reports 7, article number: 44088. (10.1038/srep44088)
2016
- Ludtmann, M. H. R., Angelova, P. R., Ninkina, N. N., Gandhi, S., Buchman, V. L. and Abramov, A. Y. 2016. Monomeric alpha-synuclein exerts a physiological role on brain ATP synthase. Journal of Neuroscience 36(41), pp. 10510-10521. (10.1523/JNEUROSCI.1659-16.2016)
- 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)
- Khatlani, T., Pradhan, S., Da, Q., Shaw, T., Buchman, V. L., Cruz, M. A. and Vijayan, K. V. 2016. A novel interaction of the catalytic subunit of protein phosphatase 2A with the adaptor protein CIN85 suppresses phosphatase activity and facilitates platelet outside-in ?IIb?3Integrin Signaling. The Journal of Biological Chemistry 291(33), pp. 17360-17368. (10.1074/jbc.M115.704296)
- Fares, M. et al. 2016. Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson's disease. Proceedings of the National Academy of Sciences 113(7), pp. E912-E921. (10.1073/pnas.1512876113)
2015
- Machhada, A. et al. 2015. Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve. Heart Rhythm 12(11), pp. 2285-2293. (10.1016/j.hrthm.2015.06.005)
- 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)
- Abramycheva, N. Y. et al. 2015. C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. Neurobiology of Aging 36(10), pp. 2908.e5-2908.e9. (10.1016/j.neurobiolaging.2015.07.004)
- Bronovitsky, E. V. et al. 2015. Gamma-carboline inhibits neurodegenerative processes in a transgenic model of amyotrophic lateral sclerosis. Doklady Biochemistry and Biophysics 462(1), pp. 189-192. (10.1134/S1607672915030138)
- Kukharsky, M. S. et al. 2015. Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis. Molecular Neurodegeneration 10, article number: 20. (10.1186/s13024-015-0014-y)
- Reed, K. R. et al. 2015. Hunk/Mak-v is a negative regulator of intestinal cell proliferation. BMC Cancer 15, article number: 110. (10.1186/s12885-015-1087-2)
- Peters, O. M. et al. 2015. Gamma-synuclein pathology in amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology 2(1), pp. 29-37. (10.1002/acn3.143)
- Robinson, H. et al. 2015. Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 16(5-6), pp. 402-409. (10.3109/21678421.2015.1040994)
2014
- Shelkovnikova, T. A., Robinson, H. K., Southcombe, J. A., Ninkina, N. and Buchman, V. L. 2014. Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Human Molecular Genetics 23(19), pp. 5211-5226. (10.1093/hmg/ddu243)
- Shelkovnikova, T., Robinson, H., Troakes, C., Ninkina, N. and Buchman, V. 2014. Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Human Molecular Genetics 23(9), pp. 2298-2312. (10.1093/hmg/ddt622)
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)
- Garcia-Reitboeck, P., Anichtchik, O., Dalley, J. W., Ninkina, N., Tofaris, G. K., Buchman, V. L. and Spillantini, M. G. 2013. Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra. Experimental Neurology 248, pp. 541-545. (10.1016/j.expneurol.2013.07.015)
- Jones, A. R. et al. 2013. Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat. Neurobiology of Aging 34(9), pp. 2234.e1-2234.e7. (10.1016/j.neurobiolaging.2013.03.003)
- 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)
- Buchman, V. L. et al. 2013. Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation. Molecular Neurodegeneration 8(1), article number: 12. (10.1186/1750-1326-8-12)
- 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)
- Millership, S. et al. 2013. Correction for Millership et al., Increased lipolysis and altered lipid homeostasis protect -synuclein-null mutant mice from diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America 110(13), pp. 5269. (10.1073/pnas.1302920110)
- 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)
- Millership, S., Ninkina, N., Rochford, J. J. and Buchman, V. L. 2013. γ-synuclein is a novel player in the control of body lipid metabolism. Adipocyte 2(4), pp. 276-280. (10.4161/adip.25162)
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)
- Millership, S. et al. 2012. Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America 109(51), pp. 20943-20948. (10.1073/pnas.1210022110)
- Samoylenko, A. et al. 2012. Increased levels of the HER1 adaptor protein Ruk(l)/CIN85 contribute to breast cancer malignancy. Carcinogenesis 33(10), pp. 1976-1984. (10.1093/carcin/bgs228)
- Peters, O. M. et al. 2012. Selective pattern of motor system damage in gamma-synuclein transgenic mice mirrors the respective pathology in amyotrophic lateral sclerosis. Neurobiology of Disease 48(1), pp. 124-131. (10.1016/j.nbd.2012.06.016)
- Shelkovnikova, T., Ninkina, N. and Buchman, V. L. 2012. In Vivo properties of mutant FUS variants. Febs Journal 279(Supp1), pp. 446-446. (10.1111/j.1742-4658.2010.08705.x)
- Kokhan, V. S. et al. 2012. Targeted inactivation of the gene encoding gamma-synuclein affects anxiety levels and investigative activity in mice. Neuroscience and Behavioral Physiology 42(6), pp. 575-581. (10.1007/s11055-012-9603-1)
- Bachurin, S. O. et al. 2012. Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice. Neurotoxicity Research 22(1), pp. 33-42. (10.1007/s12640-011-9299-y)
- Peña-Oliver, Y. et al. 2012. Deletion of alpha-synuclein decreases impulsivity in mice. Genes, Brain and Behavior 11(2), pp. 137-146. (10.1111/j.1601-183X.2011.00758.x)
- Kalinichenko, S. V., Itoh, K., Korobko, E. V., Sokol, S. Y., Buchman, V. L. and Korobko, I. V. 2012. Identification of Nedd4 E3 ubiquitin ligase as a binding partner and regulator of MAK-V protein kinase. PLoS ONE 7(6), article number: e39505. (10.1371/journal.pone.0039505)
- Ustyugov, A. A. et al. 2012. Dimebon reduces the levels of aggregated amyloidogenic protein forms in detergent-insoluble fractions in vivo. Bulletin of Experimental Biology and Medicine 152(6), pp. 731-733. (10.1007/s10517-012-1618-7)
- Shelkovnikova, T., Kulikova, A. A., Tsvetkov, P. O., Peters, O. M., Bachurin, S. O., Buchman, V. L. and Ninkina, N. 2012. Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology. Molecular Biology 46(3), pp. 362-374. (10.1134/S0026893312020161)
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)
- Guschina, I., Millership, S., O'Donnell, V. B., Ninkina, N., Harwood, J. and Buchman, V. L. 2011. Lipid classes and fatty acid patterns are altered in the brain of γ-synuclein null mutant mice. Lipids 46(2), pp. 121-130. (10.1007/s11745-010-3486-0)
- Nguyen, J. V. et al. 2011. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proceedings of the National Academy of Sciences 108(3), pp. 1176-1181. (10.1073/pnas.1013965108)
- Shelkovnikova, T., Ustyugov, A. A., Smirnov, A. P., Skvortsova, V. I., Buchman, V. L., Bachurin, S. O. and Ninkina, N. 2011. FUS gene mutations associated with familiar forms of amyotrophic lateral sclerosis affect cellular localization and aggregation properties of the encoded protein. Doklady Biochemistry and Biophysics 438(1), pp. 123-126. (10.1134/S1607672911030045)
- Shelkovnikova, T. et al. 2011. Dimebon does not ameliorate pathological changes caused by expression of truncated (1-120) human alpha-synuclein in dopaminergic neurons of transgenic mice. Neurodegenerative Diseases 8(6), pp. 430-437. (10.1159/000324989)
2010
- Venda, L. L., Cragg, S. J., Buchman, V. L. and Wade-Martins, R. 2010. α-Synuclein and dopamine at the crossroads of Parkinson's disease. Trends in Neurosciences 33(12), pp. 559-568. (10.1016/j.tins.2010.09.004)
- Greten-Harrison, B. et al. 2010. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America 107(45), pp. 19573-19578. (10.1073/pnas.1005005107)
- Korobko, I., Kalinichenko, S., Korobko, E., Ninkina, N., Kiselev, S. and Buchman, V. L. 2010. Pro-survival activity of the MAK-V protein kinase in PC12 cells [Letter]. Cell Cycle 9(20), pp. 4248-4249. (10.4161/cc.9.20.13592)
- Burre, J., Sharma, M., Tsetsenis, T., Buchman, V. L., Etherton, M. R. and Sudhof, T. C. 2010. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329(5999), pp. 1663-1667. (10.1126/science.1195227)
- Peña-Oliver, Y., Buchman, V. L. and Stephens, D. 2010. Lack of involvement of alpha-synuclein in unconditioned anxiety in mice. Behavioural Brain Research 209(2), pp. 234-240. (10.1016/j.bbr.2010.01.049)
- Havrylov, S., Redowicz, M. J. and Buchman, V. L. 2010. Emerging roles of Ruk/CIN85 in vesicle-mediated transport, adhesion, migration and malignancy. Traffic 11(6), pp. 721-731. (10.1111/j.1600-0854.2010.01061.x)
- Al-Wandi, A., Ninkina, N., Millership, S., Williamson, S. J. M., Jones, P. A. and Buchman, V. L. 2010. Absence of α-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiology of Aging 31(5), pp. 796-804. (10.1016/j.neurobiolaging.2008.11.001)
2009
- Ninkina, N., Peters, O. M., Millership, S., Salem, H. O., Van der Putten, H. and Buchman, V. L. 2009. y-Synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. Human Molecular Genetics 18(10), pp. 1779-1794. (10.1093/hmg/ddp090)
- Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., Buchman, V. L. and Ikeuchi, Y. 2009. Differential Expression of Sarcoplasmic and Myofibrillar Proteins of Rat Soleus Muscle during Denervation Atrophy. Bioscience Biotechnology and Biochemistry 73(8), pp. 1748-1756. (10.1271/bbb.90085)
- Bachurin, S. O., Ustyugov, A. A., Peters, O., Shelkovnikova, T., Buchman, V. L. and Ninkina, N. 2009. Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition enhancing compounds. Doklady Biochemistry and Biophysics 428(1), pp. 235-238. (10.1134/S1607672909050032)
- Nikolaienko, O. et al. 2009. Intersectin 1 forms a complex with adaptor protein Ruk/CIN85 in vivo independently of epidermal growth factor stimulation. Cellular Signalling 21(5), pp. 753-759. (10.1016/j.cellsig.2009.01.013)
- Yamashita, M. et al. 2009. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Letters 583(14), pp. 2419-2424. (10.1016/j.febslet.2009.06.042)
2008
- Havrylov, S., Ichioka, F., Powell, K., Borthwick, E. B., J, B., Maki, M. and Buchman, V. L. 2008. Adaptor protein Ruk/CIN85 is associated with a subset of COPI coated membranes of the Golgi complex. Traffic 9(5), pp. 798-812. (10.1111/j.1600-0854.2008.00724.x)
- Senior, S., Ninkina, N., Deacon, R., Bannerman, D., Buchman, V. L., Cragg, S. and Wade-Martins, R. 2008. Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. European Journal of Neuroscience 27(4), pp. 947-957. (10.1111/j.1460-9568.2008.06055.x)
- Mertsalov, I. B., Ninkina, N., Wanless, J. S., Buchman, V., Korochkin, L. I. and Kulikova, D. A. 2008. Generation of mutant mice with targeted disruption of two members of the d4 gene family: neuro-d4 and cer-d4. Doklady Biochemistry and Biophysics 419, pp. 65-68. (10.1134/S1607672908020051)
- Akil, O., Weber, C. M., Park, S. N., Ninkina, N., Buchman, V. and Lustig, L. R. 2008. Localization of Syncleins in the Mammalian Cochlea. JARO-Journal of the Association for Research in Otolaryngology 9(4), pp. 452-463. (10.1007/s10162-008-0134-y)
- Buchman, V. and Ninkina, N. 2008. Modulation of α-synuclein expression in transgenic animals for modelling synucleinopathies-is the juice worth the squeeze?. Neurotoxicity Research 14(4), pp. 329-341.
- Ninkina, N., Ustiugov, A. A. and Buchman, V. 2008. Modelling synucleinopathies in genetically modified animals - successes and failures. Molekulyarnaya Biologiya 42(5), pp. 747 -761. (10.1134/S0026893308050129)
- Oort, P. J. et al. 2008. y-Synuclein is an Adipocyte-Neuron Gene Coordinately-Expressed with Leptin and Increased in Human Obesity. Journal of Nutrition 135(5), pp. 841-848.
2007
- Kuhn, M., Haebig, K., Bonin, M., Ninkina, N., Buchman, V. L., Poths, S. and Riess, O. 2007. Whole genome expression analyses of single- and double-knock-out mice implicate partially overlapping functions of alpha- and gamma-synuclein. Neurogenetics 8(2), pp. 71-81. (10.1007/s10048-007-0079-z)
- Ichioka, F., Takaya, E., Suzuki, H., Kajigaya, S., Buchman, V. L., Shibata, H. and Maki, M. 2007. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Archives of biochemistry and biophysics 457(2), pp. 142-149. (10.1016/j.abb.2006.11.008)
- Korobko, I. V., Korobko, E. V., Ninkina, N., Buchman, V. L. and Kiselev, S. L. 2007. Phosphorylation of MAK-V protein kinase in mammalian cells. Doklady Biochemistry and Biophysics 412(1), pp. 37-39. (10.1134/S1607672907010115)
2006
- Papachroni, K. K. et al. 2006. Autoantibodies to alpha-synuclein in inherited Parkinson's disease. Journal of Neurochemistry 101(3), pp. 749-756. (10.1111/j.1471-4159.2006.04365.x)
- Rzhepetskyy, Y. A., Svinchuk, V. V., Mikhalap, S. V., Buchman, V. L., Sidorenko, S. P. and Drobot, L. B. 2006. Identification of protein kinases possibly involved in adaptor protein Ruk/CIN85 post-translational modification [note]. Ukrain'skyi Biokhimichnyi Zhurnal 78(6), article number: 150.
- Mayevska, O. et al. 2006. Expression of adaptor protein Ruk/CIN85 isoforms in cell lines of various tissue origins and human melanoma. Experimental Oncology 28(4), pp. 275-281.
2005
- Ilnytska, O. M. et al. 2005. Intra- and intermolecular interactions mediated by adaptor protein Ruk/CIN85/SETA. Biopolymers and Cell 21(1), pp. 48-54. (10.7124/bc.0006DB)
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2004
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2003
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2002
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2001
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2000
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Erthyglau
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- Al-Wandi, A., Ninkina, N., Millership, S., Williamson, S. J. M., Jones, P. A. and Buchman, V. L. 2010. Absence of α-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiology of Aging 31(5), pp. 796-804. (10.1016/j.neurobiolaging.2008.11.001)
- Ninkina, N., Peters, O. M., Millership, S., Salem, H. O., Van der Putten, H. and Buchman, V. L. 2009. y-Synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. Human Molecular Genetics 18(10), pp. 1779-1794. (10.1093/hmg/ddp090)
- Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., Buchman, V. L. and Ikeuchi, Y. 2009. Differential Expression of Sarcoplasmic and Myofibrillar Proteins of Rat Soleus Muscle during Denervation Atrophy. Bioscience Biotechnology and Biochemistry 73(8), pp. 1748-1756. (10.1271/bbb.90085)
- Bachurin, S. O., Ustyugov, A. A., Peters, O., Shelkovnikova, T., Buchman, V. L. and Ninkina, N. 2009. Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition enhancing compounds. Doklady Biochemistry and Biophysics 428(1), pp. 235-238. (10.1134/S1607672909050032)
- Nikolaienko, O. et al. 2009. Intersectin 1 forms a complex with adaptor protein Ruk/CIN85 in vivo independently of epidermal growth factor stimulation. Cellular Signalling 21(5), pp. 753-759. (10.1016/j.cellsig.2009.01.013)
- Yamashita, M. et al. 2009. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Letters 583(14), pp. 2419-2424. (10.1016/j.febslet.2009.06.042)
- Havrylov, S., Ichioka, F., Powell, K., Borthwick, E. B., J, B., Maki, M. and Buchman, V. L. 2008. Adaptor protein Ruk/CIN85 is associated with a subset of COPI coated membranes of the Golgi complex. Traffic 9(5), pp. 798-812. (10.1111/j.1600-0854.2008.00724.x)
- Senior, S., Ninkina, N., Deacon, R., Bannerman, D., Buchman, V. L., Cragg, S. and Wade-Martins, R. 2008. Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. European Journal of Neuroscience 27(4), pp. 947-957. (10.1111/j.1460-9568.2008.06055.x)
- Mertsalov, I. B., Ninkina, N., Wanless, J. S., Buchman, V., Korochkin, L. I. and Kulikova, D. A. 2008. Generation of mutant mice with targeted disruption of two members of the d4 gene family: neuro-d4 and cer-d4. Doklady Biochemistry and Biophysics 419, pp. 65-68. (10.1134/S1607672908020051)
- Akil, O., Weber, C. M., Park, S. N., Ninkina, N., Buchman, V. and Lustig, L. R. 2008. Localization of Syncleins in the Mammalian Cochlea. JARO-Journal of the Association for Research in Otolaryngology 9(4), pp. 452-463. (10.1007/s10162-008-0134-y)
- Buchman, V. and Ninkina, N. 2008. Modulation of α-synuclein expression in transgenic animals for modelling synucleinopathies-is the juice worth the squeeze?. Neurotoxicity Research 14(4), pp. 329-341.
- Ninkina, N., Ustiugov, A. A. and Buchman, V. 2008. Modelling synucleinopathies in genetically modified animals - successes and failures. Molekulyarnaya Biologiya 42(5), pp. 747 -761. (10.1134/S0026893308050129)
- Oort, P. J. et al. 2008. y-Synuclein is an Adipocyte-Neuron Gene Coordinately-Expressed with Leptin and Increased in Human Obesity. Journal of Nutrition 135(5), pp. 841-848.
- Kuhn, M., Haebig, K., Bonin, M., Ninkina, N., Buchman, V. L., Poths, S. and Riess, O. 2007. Whole genome expression analyses of single- and double-knock-out mice implicate partially overlapping functions of alpha- and gamma-synuclein. Neurogenetics 8(2), pp. 71-81. (10.1007/s10048-007-0079-z)
- Ichioka, F., Takaya, E., Suzuki, H., Kajigaya, S., Buchman, V. L., Shibata, H. and Maki, M. 2007. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Archives of biochemistry and biophysics 457(2), pp. 142-149. (10.1016/j.abb.2006.11.008)
- Korobko, I. V., Korobko, E. V., Ninkina, N., Buchman, V. L. and Kiselev, S. L. 2007. Phosphorylation of MAK-V protein kinase in mammalian cells. Doklady Biochemistry and Biophysics 412(1), pp. 37-39. (10.1134/S1607672907010115)
- Papachroni, K. K. et al. 2006. Autoantibodies to alpha-synuclein in inherited Parkinson's disease. Journal of Neurochemistry 101(3), pp. 749-756. (10.1111/j.1471-4159.2006.04365.x)
- Rzhepetskyy, Y. A., Svinchuk, V. V., Mikhalap, S. V., Buchman, V. L., Sidorenko, S. P. and Drobot, L. B. 2006. Identification of protein kinases possibly involved in adaptor protein Ruk/CIN85 post-translational modification [note]. Ukrain'skyi Biokhimichnyi Zhurnal 78(6), article number: 150.
- Mayevska, O. et al. 2006. Expression of adaptor protein Ruk/CIN85 isoforms in cell lines of various tissue origins and human melanoma. Experimental Oncology 28(4), pp. 275-281.
- Ilnytska, O. M. et al. 2005. Intra- and intermolecular interactions mediated by adaptor protein Ruk/CIN85/SETA. Biopolymers and Cell 21(1), pp. 48-54. (10.7124/bc.0006DB)
- Surgucheva, I., Ninkina, N., Buchman, V. L., Grasing, K. and Surguchov, A. 2005. Protein aggregation in retinal cells and approaches to cell protection. Cellular and Molecular Neurobiology 25(6), pp. 1051-1066. (10.1007/s10571-005-8474-1)
- Papachroni, K., Ninkina, N., Wanless, J., Kalofoutis, A. T., Gnuchev, N. V. and Buchman, V. L. 2005. Peripheral sensory neurons survive in the absence of α- and γ-synucleins. Journal of Molecular Neuroscience 25(2), pp. 157-164. (10.1385/JMN:25:2:157)
- Simonova, O. B., Kulikova, D. A., Mertsalov, I. B., Umnova, O. N., Bashkirov, V. N., Buchman, V. L. and Korochkin, L. I. 2005. Analysis of the overexpression of a newly found gene toothrin in Drosophila. Russian Journal of Genetics 41(2), pp. 138-143. (10.1007/s11177-005-0037-5)
- Mayevska, O. M. et al. 2005. Monoclonal and polyclonal antibodies produced against adaptor/scaffold protein Ruk/CIN85/SETA: characterization and practical applications. Ukrain'skyi Biokhimichnyi Zhurnal 77(2), article number: 211.
- Borthwick, E. B. et al. 2004. Multiple Domains of Ruk/CIN85/SETA/CD2BP3 are Involved in Interaction with p85α Regulatory Subunit of PI 3-kinase. Journal of Molecular Biology 343(4), pp. 1135-1146. (10.1016/j.jmb.2004.08.075)
- Robertson, D. C., Schmidt, O., Ninkina, N., Jones, P. A., Sharkey, J. and Buchman, V. 2004. Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of γ-synuclein, α-synuclein and double α/γ- synuclein null mutant mice. Journal of Neurochemistry 89(5), pp. 1126-1136. (10.1111/j.1471-4159.2004.02378.x)
- Saha, A. R. et al. 2004. Parkinson's disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons. Journal of Cell Science 117(Pt 7), pp. 1017-1024. (10.1242/jcs.00967)
- Ruzov, A. S., Meehan, R., Kiselev, S. L., Buchman, V. L., Korobko, I. V. and Mertsalov, I. B. 2004. Cloning and developmental expression of MARK/Par-1/MELK-related protein kinase xMAK-V in Xenopus laevis. Development Genes and Evolution 214(3), pp. 139-143. (10.1007/s00427-004-0381-9)
- Ninkina, N. et al. 2003. Neurons Expressing the Highest Levels of γ-Synuclein Are Unaffected by Targeted Inactivation of the Gene. Molecular and Cellular Biology 23(22), pp. 8233-8245. (10.1128/MCB.23.22.8233-8245.2003)
- Dev, K. K., Hofele, K., Barbieri, S., Buchman, V. L. and van der Putten, H. 2003. Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45(1), pp. 14-44. (10.1016/S0028-3908(03)00140-0)
- Kit, Y. Y. et al. 2003. Adaptor protein Ruk1 forms protein-protein complexes with endonuclease activity in HEK293 cells. Biochemistry (Moscow) 68(7), pp. 810-815.
- Orel, V. R. et al. 2002. Subcellular localization of adapter protein Ruk, in HEK293 cells. Biopolymers and Cell 18(4), pp. 312-318. (10.7124/bc.000611)
- Verdier, F., Valovka, T., Zhyvoloup, A., Drobot, L. B., Buchman, V. L., Waterfield, M. and Gout, I. 2002. Ruk is ubiquitinated but not degraded by the proteasome. European Journal of Biochemistry 269(14), pp. 3402-3408. (10.1046/j.1432-1033.2002.03031.x)
- Buchman, V. L., Luke, C., Borthwick, E. B., Gout, I. and Ninkina, N. 2002. Organization of the mouse Ruk locus and expression of isoforms in mouse tissues. Gene 295(1), pp. 13-17. (10.1016/S0378-1119(02)00821-1)
- Nabirochkina, E., Simonova, O. B., Mertsalov, I. B., Kulikova, D. A., Ladigina, N. G., Korochkin, L. I. and Buchman, V. L. 2002. Expression pattern of dd4, a sole member of the d4 family of transcription factors in Drosophila melanogaster. Mechanisms of Development 114(1-2), pp. 119-123. (10.1016/S0925-4773(02)00035-7)
- Orike, N., Middleton, G., Borthwick, E., Buchman, V. L., Cowen, T. and Davies, A. M. 2001. Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. Journal of cell biology, pp. 995-1005. (10.1083/jcb.200101068)
- Alonzi, T. et al. 2001. Role of STAT3 and PI 3-Kinase/Akt in mediating the survival actions of cytokines on sensory neurons. Molecular and Cellular Neuroscience 18(3), pp. 270-282. (10.1006/mcne.2001.1018)
- Ninkina, N. et al. 2001. Cerd4, third member of the d4 gene family: expression and organization of genomic locus. Mammalian Genome 12(11), pp. 862-866. (10.1007/s00335-001-3039-1)
- Saha, A. R., Ninkina, N. N., Hanger, D. P., Anderton, B. H., Davies, A. M. and Buchman, V. L. 2000. Induction of neuronal death by alpha-synuclein. European Journal of Neuroscience 12(8), pp. 3073-3077. (10.1046/j.1460-9568.2000.00210.x)
- Tiunova, A. . A. et al. 2000. Chicken synucleins: cloning and expression in the developing embryo. Mechanisms of Development 99(1-2), pp. 195-198. (10.1016/S0925-4773(00)00484-6)
- Mertsalov, I. B., Kulikova, D. A., Alimova-Kost, M. V., Ninkina, N. N., Korochkin, L. I. and Buchman, V. L. 2000. Structure and expression of two members of the d4 gene family in mouse. Mammalian Genome 11(1), pp. 72-74. (10.1007/s003350010014)
- Ninkina, N. and Buchman, V. L. 2000. Synucleins: to have or not to have?. Russian Journal of Genetics 36(11), pp. 1487-1491.
- Gout, I. et al. 2000. Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. Embo Journal 19(15), pp. 4015-4025.
- Mertsalov, I. V., Kulikova, D. A., Ninkina, N., Simonova, O. B., Buchman, V. L. and Korochkin, L. 2000. Genomic organization of the mouse neuro-d4 gene. Russian Journal of Genetics 3(36), pp. 241-244.
- Ninkina, N. and Buchman, V. L. 2000. Synucleins: to have or not to have?. Russian Journal of Genetics 36(11), pp. 1487-1491.
- Mertsalov, I. V., Kulikova, D. A., Ninkina, N., Simonova, O. B., Buchman, V. L. and Korochkin, L. 2000. Genomic organization of the mouse neuro-d4 gene. Russian Journal of Genetics 3(36), pp. 241-244.
Ymchwil
Projectau
bioleg Synuclein
Daeth synucleins i'r amlwg ym 1997 ar ôl i'r astudiaethau cyntaf gael eu cyhoeddi sy'n cysylltu treigladau missense yn yr SNCA, genyn sy'n amgodio alffa-synuclein, â ffurf deuluol o glefyd Parkinson, ac agregu alffa-synuclein i newidiadau histopatholegol sy'n nodweddiadol o'r rhan fwyaf o achosion clefyd Parkinson. Er gwaethaf y lefel uchel o ddiddordeb a ysgogwyd gan y canfyddiadau hyn, ni ddeellir swyddogaeth arferol alffa-synuclein, nac union fecanwaith newidiadau patholegol a achosir gan ei gamweithrediad yn dda. Hyd yn oed llai hysbys am swyddogaeth dau aelod arall o'r teulu, beta-synuclein a gama-synuclein, mewn iechyd a chlefydau. Mae'r gymuned ymchwil yn dal i wynebu anawsterau wrth ddehongli'r canlyniadau a gafwyd mewn llawer o labordai gan ddefnyddio gwahanol systemau arbrofol, yn bennaf oherwydd priodweddau strwythurol anghonfensiynol syncleinau, eu cyfranogiad mewn prosesau mewngellol lluosog, effaith wahaniaethol gwahanol isofformau protein (monomerau, oligomers, protofibrilau a ffibriliau) ar y prosesau hyn a diswyddo swyddogaethol o fewn y teulu. Felly, mae astudiaethau manwl pellach o bob agwedd ar fioleg syniwclewin mewn systemau arbrofol mwy priodol yn hanfodol ar gyfer deall rôl y proteinau hyn mewn systemau nerfol normal a dirywiol. Ar hyn o bryd, rydym yn cymryd rhan mewn nifer o brosiectau a allai helpu i gyflawni'r amcanion hyn:
Swyddogaeth arferol synucleins
i. Wrth drosglwyddo synaptig
Yn ddiweddar, rydym wedi cynhyrchu llygod heb aelodau o'r teulu syniwclin ym mhob cyfuniad posibl (un, dwbl a triple knock-outs) ac wedi cyflogi'r modelau hyn i ddatgelu pwysigrwydd y proteinau hyn wrth fodiwleiddio rhyddhau neurotransmitter mewn gwahanol fathau o niwronau (er enghraifft gweler Ffigur 1). Mae gennym hefyd dystiolaeth o gyfranogiad synucleins mewn cymeriant niwrodrosglwyddydd gan fesiglau presynaptig ac ar hyn o bryd rydym yn astudio union fecanwaith yr effaith hon.
ii. Yn natblygiad niwronau dopaminergic midbrain.
Awgrymodd ein canlyniadau blaenorol rôl wahaniaethol i aelodau teulu syniwclewin yn y broses hon, a bodolaeth rhai mecanweithiau a allai wneud iawn am gamweithrediad y proteinau hyn yn ystod cyfnodau datblygiadol critigol. Ar hyn o bryd, rydym yn astudio sut y gallai'r newidiadau hyn effeithio ar sensitifrwydd niwronau dopaminergig oedolion i wahanol heriau niwrotocsig.
iii. Wrth gynhyrchu ynni mitochondria.
Er bod synucleins bob amser yn cael eu hystyried i fod yn rhan o swyddogaeth arferol mitocondria ymennydd, nid yw'n glir o hyd pa elfennau o'r gadwyn gynhyrchu ynni y gellid eu modiwleiddio gan y proteinau hyn. Er mwyn mynd i'r afael â'r cwestiwn hwn, rydym yn cymhwyso gwahanol ddulliau biocemegol, bioffisegol a ffarmacolegol i asesu effeithiau pob syncl ar swyddogaeth mitochondrial. Mae'r astudiaethau hyn yn cael eu cynnal ar mitocondria puro, diwylliannau celloedd niwronau a sleisys ymennydd a geir o lygod cnoclein amrywiol . Rydym hefyd yn ailgyflwyno synucleins i niwronau diwylliedig trwy gyflwyno lentifiraol, neu drwy ychwanegu synleins ailgyfunol monomerig swyddogaethol i adweithiau in vitro.
iv. Mewn bioleg adipocyte (gama-synuclein).
Yn ogystal â mynegiant cadarn yn y system nerfol, yn enwedig mewn niwronau synhwyraidd ac isaf y synhwyrau ymylol, mae gama-synuclein yn doreithiog mewn meinwe adipose gwyn. Rydym wedi dangos rheoleiddio dietegol o fynegiant gama-synuclein mewn adipocytes ac achub llygod o ordewdra braster uchel a ffenoteip metabolig trwy guro'r genyn gama-synuclein. Mae ein data yn cefnogi'r rhagdybiaeth bod disbyddiad gama-synuclein yn cynyddu lefel y lipolisis mewn adipocytes mewn amodau gormodedd maetholion, o bosibl trwy fodiwleiddio gweithgaredd ATGL ac ymasiad diferion lipid (Ffigur 2). Dylai astudiaethau manwl parhaus o'r mecanweithiau hyn ddatgelu a ellir ystyried gama-synuclein fel targed addawol ar gyfer therapi gordewdra a syndrom metabolig.
Synucleins mewn prosesau patholegol
i. Cytotoxicity o gyfryngu agregu alffa-synuclein.
Rydym yn astudio gwenwyndra gwahanol gyfryngu neu gynhyrchion terfynol o agregu alffa-syniwclewin ailgyfunol wedi'i buro i wahanol fathau o niwronau, gan gynnwys niwronau o lygod cnewyllyn synclein. Defnyddir y rhywogaethau alffa-synuclein hyn hefyd i asesu eu heffeithiau ar swyddogaeth mitocondria, fel y disgrifir uchod.
ii. Ennill gwenwynig o swyddogaeth gama-synuclein mewn niwronau modur a'i rôl mewn clefyd niwronau motor.
Yn ddiweddar, rydym wedi disgrifio proffiliau patholegol newydd gama-synuclein-positif yn llwybr cortico-asgwrn cefn is-set o gleifion ALS. Awgrymom fod y strwythurau hyn yn cynrychioli agregau gama-synuclein a ffurfiwyd wrth ddiraddio echelinau niwronau modur uchaf, ac felly, gallai agregiad patholegol gama-synuclein fod yn rhan o bathogenesis o ffurfiau neu gamau penodol o'r clefyd. Yn gyson, llygod sy'n gorfynegi llygod math gwyllt gama-synuclein llygoden mewn niwronau yn datblygu ffenoteip modur sy'n ddibynnol ar oedran a genynnau a achosir gan agregu gama-synuclein mewn cyrff ac axons celloedd niwronau ac yna dirywiad dethol o rai poblogaethau niwronau modur penodol (Ffigur 3). Ein nod nesaf yw datgelu'r gadwyn o ddigwyddiadau sy'n arwain at gamweithrediad niwronau a marwolaeth yn y model hwn o ALS ac egluro tarddiad a chyfansoddiad proffiliau gama-synuclein patholegol cadarnhaol yn system nerfol cleifion ALS.
iii. Disbyddiad sy'n ddibynnol ar oedran o synucleins swyddogaethol o synapsau niwronau a'i gyfraniad at niwrodrosglwyddiad dan fygythiad.
Mae'n ymarferol bod agregu patholegol enfawr o alffa-synuclein mewn corff celloedd niwron ac axons cleifion clefyd y corff Parkinson a Lewy yn arwain at ddifa dwfn terfynellau presynaptig o alffa-synuclein swyddogaethol. Gallai hyn beryglu niwrodrosglwyddiad synaptig arferol a chyfrannu at amlygu symptomau clefydau. Mewn llygod sy'n deillio o'r genyn, gellir niwtraleiddio'r effaith hon gan rai mecanweithiau iawndal yn ystod cyfnodau critigol y datblygiad (gweler uchod). Er mwyn neidio hyn, rydym wedi cynhyrchu llygod yn ddiweddar lle gellir anactifadu'r genyn alffa-synuclein yn amodol mewn poblogaethau niwronau dethol ac ar unrhyw gam datblygiadol, gan gynnwys anifeiliaid sy'n heneiddio (Ffigur 4). Bydd astudiaethau o'r llygod hyn yn datgelu rôl diffyg alffa-synuclein swyddogaethol wrth ddatblygu symptomau sy'n nodweddiadol ar gyfer synucleinopathïau.
iv. Gamma-synuclein mewn tiwmorigenesis a maligneiddio.
Yn ogystal â meinweoedd adipose niwral a gwyn, mae llawer o gama-synuclein i'w gael yn aml mewn mathau penodol o diwmorau, yn enwedig ar gamau ymlaen llaw o falaen. Nid astudiwyd y ffenomen hon yn iawn, ond awgrymwyd mewn llenyddiaeth, bod gama-synuclein yn ymwneud â dilyniant tiwmorau chwarren mammari. Gwelsom gydberthynas rhwng mynegiant gama-synuclein ac Erb2B yn y math hwn o diwmor a llinellau celloedd tiwmor. Fodd bynnag, mae ein hastudiaethau o diwmorynnau mamari a metastasis a achosir gan Erb2B ym mhresenoldeb ac absenoldeb gama-synuclein yn dangos nad oes angen y protein hwn ar gyfer y naill neu'r llall o'r prosesau hyn, o leiaf yn y math hwn o diwmorau. Dylai astudiaethau pellach ddatgelu pam mae gama-synuclein yn dod yn arwydd o rai tiwmorau cam ymlaen llaw.
Perthynas rhwng metaboledd RNA ac agregiad patholegol o broteinau RNA rhwymo wrth ddatblygu ALS a chlefydau cysylltiedig
Mae nifer sylweddol o dreigladau sy'n gysylltiedig ag ALS wedi'u nodi mewn genynnau sy'n amgodio proteinau RNA-rwymol. Ar ben hynny, mae gan rai o'r proteinau hyn barthau tebyg i prion-sy'n gyfrifol am eu tueddiad uchel i gyfuno. Yn gyson, canfuwyd agregau patholegol a ffurfiwyd gan y proteinau hyn yn system nerfol ALS teuluol ac ysbeidiol a rhai afiechydon niwroddirywiol eraill. Felly, ystyrir metaboledd RNA dan fygythiad a chydgrynhoi protein patholegol fel achosion posibl niwroddirywio, ond nid yw cyfraniad at ddatblygiad patholeg a pherthynas rhwng y prosesau hyn yn cael eu deall yn dda eto. Er mwyn egluro hyn, rydym ar hyn o bryd yn defnyddio modelau celloedd ac anifeiliaid amrywiol i astudio FUS, un o broteinau RNA sy'n rhwymo sy'n ymwneud â pathogenesis ALS a chlefydau cysylltiedig, ac yn bwriadu ymestyn yr astudiaethau hyn i broteinau RNA eraill sy'n rhwymo'n ddiweddar iawn â'r clefydau hyn, sef hnRNPA1 a hnRNPA2/B1.
Mecanwaith agregu patholegol o brotein FUS mewn celloedd
Mae ein hastudiaethau o leoleiddio mewngellog a ffurfio strwythurau annodweddiadol (puncta bach neu fwy, aggresomes, ac ati) gan wahanol fathau wedi'u haddasu o brotein FUS dynol mewn nifer o linellau celloedd sefydlog, wedi dangos bod FUS yn dod yn agregiad hynod dueddol pan nad yw'n gallu rhwymo RNA targed (Ffigur 5). Yn seiliedig ar yr arsylwadau hyn, gwnaethom awgrymu rhagdybiaeth o agregu patholegol o FUS (llawysgrif sy'n cael ei hadolygu).
Modelau anifeiliaid o FUSopathies
Er mwyn ymestyn ein hastudiaethau o agregu FUS i system fwy perthnasol in vivo, rydym wedi cynhyrchu llygod trawsgenig sy'n mynegi ffurf C-derfynol truncated o FUS dynol yn eu niwronau. Mae'r llygod hyn yn datblygu'n sydyn patholeg echddygol ddifrifol yn 2.5 - 4.5 mis, a nodweddir gan agregiad dwys o FUS llygoden dynol ac endogenaidd ym mhob adran niwronau, a difrod difrifol poblogaethau dethol o niwronau modur a'u axons (papur yn y wasg). Mae llinellau llygoden eraill sy'n mynegi amrywiadau gwahanol o FUS hefyd wedi'u cynhyrchu, ac mae astudiaethau o'u ffenoteipiau ar y gweill.
Pysgota ffisiolegol a phathologol FUS a phroteinau RNA eraill agregiad sy'n dueddol o rwymo RNA mewn cyfadeiladau niwclear a sytoplasmig RNP
Mae'r proteinau hyn yn drigolion cyfadeiladau RNP niwclear a cytoplasmig amrywiol mewn celloedd normal ac mae eu galluoedd i gysylltu â'r cymhlethdodau hyn yn aml yn cael eu peryglu wrth ddifodi niwronau. Fodd bynnag, nid yw swyddogaeth pob protein ym mhob cyfadeilad RNP yn glir. Nod ein hastudiaethau yw datgelu'r swyddogaethau hyn a'u cysylltu â newidiadau patholegol yn ALS a chlefydau niwroddirywiol eraill.
Ailadrodd ehangiadau yn y locws genomig C9ORF72 fel ffactor etiolegol ar gyfer ALS a chlefydau cysylltiedig
Ehangu repeats GGGGCC yn y locws C9ORF72 yw'r mwtaniad mwyaf cyffredin mewn cleifion ALS, ond mae mecanweithiau moleciwlaidd datblygu patholeg yn dal i fod yn aneglur. Mewn cydweithrediad â chydweithwyr o'r Sefydliad Niwroleg, Coleg y Brenin Llundain, a Sefydliad Niwrowyddoniaeth Drosiadol Sheffield, rydym yn astudio effeithiau'r maint ailadrodd ar ddechrau, amlygiadau clinigol a pharamedrau eraill y clefyd, (Ffigur 6).
Parthau swyddogaethol modulatyddion trawsgrifio niwrospecific sy'n perthyn i'r teulu D4 / DPF / BAF45
Mae tri genyn yn cynnwys y teulu D4 o modulatyddion trawsgrifio, ond mae hyrwyddwyr amgen a digwyddiadau splicing yn cynhyrchu amrywiaeth fawr o broteinau amgodio gyda chyfansoddiad gwahanol o barthau strwythurol. Mae aelodau niwro-benodol o'r teulu protein D4 (niwro-d4 / BAF45b a cer-d4 / BAF45c) yn gydrannau o gymhleth ailfodelu cromatig mawr mewn niwronau gwahaniaethol. Mae data presennol yn awgrymu bod newid datblygiadol o gelloedd cynhenid niwronau i niwronau ymroddedig yn gofyn am amnewid protein BAF45a sy'n gysylltiedig ychydig yn gysylltiedig â phroteinau D4 yn y cymhleth hwn. Rydym yn astudio rôl gwahanol barthau strwythurol o broteinau D4 mewn rhyngweithio â chydrannau cromatotin a ffosffolipidau. Rydym hefyd wedi cynhyrchu llygod sy'n mynegi C-derfynol yn unig, hy heb barthau bysedd PHD dwbl pwysig, fersiynau o broteinau niwro-d4 / BAF45b a cer-d4 / BAF45c. Er bod llygod mwtant sengl a dwbl yn hyfyw, mae'r olaf yn datblygu rhai annormaleddau ymddygiadol.
Staff cysylltiedig
Myfyrwyr ymchwil ôl-raddedig
- Mrs Haiyan An (myfyriwr PhD)
Cyn-fyfyrwyr ac aelodau o labordy Caerdydd
- Dr. Owen Peters (myfyriwr PhD, yna postdoc 2007-2012, gradd PhD a ddyfarnwyd yn 2011, ar hyn o bryd postdoc yn labordy Robert H. Brown, Jr., Ysgol Feddygol Prifysgol Massachusetts)
- Dr. Steven Millership (Cynorthwy-ydd Ymchwil, myfyriwr PhD rhan-amser, yna postdoc 2007-2012, gradd PhD a ddyfarnwyd yn 2012, ar hyn o bryd postdoc yn y Grŵp Signalau Metabolaidd, Coleg Imperial, Llundain)
- Dr. Essam Sharfeddin (myfyriwr PhD 2008-2012, gradd PhD a ddyfarnwyd yn 2013, dychwelodd i'r Sefydliad yn Libya a gefnogodd ei Raglen PhD yn y DU)
- Dr. Natalie Connor-Robson (myfyriwr PhD 2009-2012, gradd PhD a ddyfarnwyd yn 2013, sydd ar hyn o bryd yn Gymrawd Datblygu Gyrfa yng Nghanolfan Clefyd Parkinson Rhydychen, Prifysgol Rhydychen)
Cymorth grant cyfredol
- Grant Prosiect Parkinson's UK
- Michael J. Fox Foundation Gwobr Arloesi Ymateb Cyflym
- Grant Prosiect Cymdeithas Alzheimer
- Grant Prosiect Cymdeithas Clefyd Motor Niwron
Cydweithredwyr
- Yr Athro Thomas Südhof, Prifysgol Stanford, UDA (swyddogaeth ffisiolegol syncleins)
- Dr. Herman van der Putten, Novartis Pharma, Basel, Y Swistir (synucleins a niwroddirywio)
- Yr Athro Michel Goedert, MRC LMB, Caergrawnt, y DU (agregiad protein patholegol)
- Yr Athro Maria Spillantini, Prifysgol Cambrudge, y DU (alpha-synuclein yn natblygiad niwronau dopaminergig)
- Yr Athro Olaf Riess, Prifysgol Tübingen, yr Almaen (swyddogaeth ffisiolegol syncleins)
- Dr. Justin J. Rochford, Prifysgol Aberdeen, y DU (gama-synuclein mewn bioleg adipocyte)
- Dr. Nicholas Marsh-Armstrong, Prifysgol John Hopkins, Baltimore, UDA (gama-synuclein yn swyddogaeth a chamweithrediad y system optig)
- Yr Athro Andrey Abramov, Coleg Prifysgol Llundain, y DU (swyddogaeth mitocondrial a chamweithrediad synucleins)
- Dr. Richard Wade-Martins, Dr. Stephanie J. Cragg, a'r Athro J. Peter Bolam, Prifysgol Rhydychen, y DU (swyddogaeth synucleins mewn niwrodrosglwyddiad dopamin)
- Dr. Sreeganga S. Chandra, Prifysgol Yale, UDA (swyddogaeth ffisiolegol syncleins)
- Yr Athro David N.Stephens, Prifysgol Sussex, Brighton, y DU (effeithiau disbyddu alffa-synclél ar ymddygiad anifeiliaid)
- Dr. Natalia Ninkina, Prifysgol Caerdydd, y DU (synucleins a phroteinau RNA rhwymo mewn clefydau dynol)
- Yr Athro Alun Davies, Prifysgol Caerdydd, y DU (llwybrau trawsyrru signal ynghlwm wrth wahaniaethu niwronau)
- Yr Athro Alan Clarke, Prifysgol Caerdydd, DU (MAK-V/Hunk kinase mewn celloedd tiwmor)
- Yr Athro Ivan Gout, Coleg Prifysgol Llundain (isofformau Ruk mewn signalau mewngellol)
- Yr Athro Masatoshi Maki, Prifysgol Nagoya, Japan (isofformau Ruk mewn masnachu bilen)
- Dr. Ludmila Drobot, Sefydliad Bioleg Celloedd, Lviv, Wcráin (isofformau Ruk mewn celloedd tiwmor)
- Drs Elena ac Igor Korobko, Sefydliad Bioleg Genynnau, Moscow, Rwsia (rhyngweithiadau mewn-a rhyngfoleciwlaidd o broteinau Ruk; rôl MAK-V kinase mewn datblygiad a ffisioleg llygoden)
- Drs Ilja Mertsalov, Dina Kulikova ac Olga Simonova, Sefydliad Bioleg Genynnau, Moscow, Rwsia (astudiaethau swyddogaethol o aelodau teulu D4 mewn llygod a Drosophila)
- Yr Athro Pamela J. Shaw, Sefydliad Niwrowyddoniaeth Drosiadol Sheffield, y DU (ail-ehangu GGGGCC mewn ALS a chlefydau cysylltiedig)
- Yr Athro Amar Al-Chalabi, Sefydliad Niwroleg, Coleg y Brenin Llundain, y DU (C9ORF72 treigladau locus mewn ALS teuluol)
- Yr Athro Sergey O. Bachurin, Sefydliad Cyfansoddion Ffisiolegol Gweithredol Chernogolovka, Rwsia (gama-carbolines fel cyffuriau addasu clefyd niwroddirywiol)
Contact Details
BuchmanVL@caerdydd.ac.uk
+44 29208 79068
Adeilad Syr Martin Evans, Ystafell Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX
+44 29208 79068
Adeilad Syr Martin Evans, Ystafell Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX