Experimental justification for the possibility of prediction of the development of neurodegenerative diseases following gamma-sinuclein dysfunction based on the influence of dopaminergic system on the intraocular pressure.
Keywords:
neurodegenerative diseases, gamma-syinucleinopathy, intraocular pressure, dopaminergic system regulators, knock-out mice.
Abstract
Synucleins are a family of synaptic proteins involved in vesicular transport and release of neurotransmitters, particularly dopamine. Pathological aggregation of these proteins is associated with development of several neurodegenerative diseases (NDD), and gamma-synuclein was shown to be related with glaucoma. At present, there are no available diagnostic methods for identifying groups at risk of NDD or other diseases related with γ-synuclein dysfunction by the effect of adrenergic and dopaminergic regulators on intraocular pressure (IOP). A difficulty in developing such methods is that NDDs are diagnosed by clinical symptoms when the process is already practically irreversible. The aim of this study was experimental justification of a possibility for predicting the γ-synuclein dysfunction by the effect of adrenergic and dopaminergic regulators on IOP. Methods. A strain of knockout mice with inactivated gamma-synuclein gene (gamma-KO) was used for developing a method for detection of γ-synuclein dysfunction. The method included measurement of IOP before and after instillation of drugs regulating the dopaminergic system activity. Results. Gamma-KO mice showed a statistically significant decrease in IOP following the instillation of 0.1% Melatonin, 0.2% Haloperidol, or 10% Dopamine compared to the wild type control. Conclusion. The suggested method allows detecting and predicting the development of γ-synuclein dysfunction and its influence on the IOP regulation and, thus, to identify groups of risk to be monitored and preventively treated.
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References
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2. Ugrjumov M.V. Nejrodegenerativnye zabolevanija: ot genoma do celostnogo organizma. M.: Nauchnyj mir; 2014: 22-44. (in Russian)
3. Collier T.J., Redmond D.E., Steece-Collier K., Lipton J.W., Manfredsson F.P. Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates. Front Neurosci. 2016; 29: 10-12. doi: 10.3389/fnins.2016.00012.
4. Sanjeev A., Mattaparthi V.K.. Computational Study on the Role of γ-Synuclein in Inhibiting the α-Synuclein Aggregation. Cent Nerv Syst Agents Med Chem. 2019; 19(1): 24-30. doi: 10.2174/1871524918666181012160439.
5. Tarasova T.V., Ustyugov A.A., Ninkina N.N., Skvortsova V.I. The new line of genetically modified mice with constitutive knock out of the gene alpha synuclein to study pathogenetic aspects of differential loss of dopaminergic neurons. Patologicheskaya Fiziologiya i Eksperimental`naya terapiya.(Pathlogical Physiologyand Experimental Therapy, Russian Journal). 2016; 60(3): 4-9. (in Russian)
6. Anwar S., Peters O., Millership S., Ninkina N., Doig N., Connor-Robson N., Threlfell S., Kooner G., Deacon R.M., Bannerman D.M., Bolam J.P., Chandra S.S., Cragg S.J., Wade-Martins R., Buchman V.L. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. J Neurosci. 2011; 31(20):7264-74. doi: 10.1523/JNEUROSCI.6194-10.2011.
7. Burré J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Südhof T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010; 329:1663-7. doi: 10.1126/science.1195227.
8. Millership S., Ninkina N., Guschina I.A., Norton J., Brambilla R., Oort P.J., Adams S.H., Dennis R.J., Voshol P.J., Rochford J.J., Buchman V.L., Increased lipolysis and altered lipid homeostasis protect γ-synuclein null mutant mice from diet-induced obesity. Proc Natl Acad Sci USA. 2012; 18: 109(51): 20943-8. doi: 10.1073/pnas.1210022110.
9. Vargas K.J., Makani S., Davis T., Westphal C.H., Castillo P.E., Chandra S.S. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci. 2014; 34(28):9364-76. doi: 10.1523/JNEUROSCI.4787-13.2014.
10. Buchman V.L., Adu J., Pinon L.G., Ninkina N.N., Davies A.M. Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat Neurosci. 1998; 1(2): 101-3. doi: 10.1038/349.
11. Ninkina N., Papachroni K., Robertson D.C., Schmidt O., Delaney L., O'Neill F., Court F., Rosenthal A., Fleetwood-Walker S.M., Davies A.M., Buchman V.L. Neurons expressing the highest levels of gamma-synuclein are unaffected by targeted inactivation of the gene. Mol Cell Biol. 2003; 23(22): 8233-45. doi: 10.1128/mcb.23.22.8233-8245.2003.
12. Peters O.M., Shelkovnikova T., Highley J.R., Cooper-Knock J., Hortobágyi T., Troakes C., Ninkina N., Buchman V.L. Gamma-synuclein pathology in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2015; 2(1): 29-37. doi: 10.1002/acn3.143.
13. Peters O.M., Millership S., Shelkovnikova T.A., Soto I., Keeling L., Hann A., Marsh-Armstrong N., Buchman V.L., Ninkina N. Selective pattern of motor system damage in gamma-synuclein transgenic mice mirrors the respective pathology in amyotrophic lateral sclerosis. Neurobiol Dis. 2012; 48(1): 124-31. doi: 10.1016/j.nbd.2012.06.016.
14. Ninkina N., Peters O., Millership S., Salem H., van der Putten H., Buchman V.L. Gamma-synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. Hum Mol Genet. 2009; 15; 18(10): 1779-94. doi: 10.1093/hmg/ddp090.
15. Galvin J.E., Giasson B., Hurtig H.I., Lee V.M., Trojanowski J.Q. Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol. 2000; 157(2): 361-8. doi: 10.1016/s0002-9440(10)64548-8.
16. Galvin J.E., Uryu K., Lee V.M., Trojanowski J.Q. Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc Natl Acad Sci U S A. 1999; 96(23): 13450-5. doi: 10.1073/pnas.96.23.13450.
17. Surgucheva I., McMahan B., Ahmed F., Tomarev S., Wax M.B., Surguchov A. Synucleins in glaucoma: implication of gamma-synuclein in glaucomatous alterations in the optic nerve. J Neurosci Res. 2002; 68(1): 97-106. doi: 10.1002/jnr.10198.
18. Surgucheva I., Ninkina N., Buchman V.L., Grasing K., Surguchov A. Protein aggregation in retinal cells and approaches to cell protection. Cell Mol Neurobiol. 2005; 25(6): 1051-66.
19. Surguchov A., McMahan B., Masliah E., Surgucheva I. Synucleins in ocular tissues. J Neurosci Res. 2001; 65(1): 68-77. doi: 10.1002/jnr.1129.
20. Senior S.L., Ninkina N., Deacon R., Bannerman D., Buchman V.L., Cragg S.J. Wade-Martins R. Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. Eur J Neurosci. 2008; 27(4): 947-57. doi: 10.1111/j.1460-9568.2008.06055.x.
21. Pescosolido N., Parisi F., Russo P., Buomprisco G., Nebbioso M. Role of dopaminergic receptors in glaucomatous disease modulation. Biomed Res Int. 2013; 2013: 193048. doi: 10.1155/2013/193048.
22. Strahov V.V., Ermakova A.V., Popova A.A., Korchagin N.V. Issledovanie mezhokulyarnoj asimmetrii – vazhnyj instrument v diagnostike i monitoringe pervichnoj glaukomy. RMZH «Klinicheskaya Oftal'mologiya». 2014; 2: 93. (in Russian)
23. Levin O.S., Amosova N.A. Differencial'naya diagnostika atipichnogo parkinsonizma. Diagnostika i lechenie ekstrapiramidnyh rasstrojstv. M; 2000: 71–83. (in Russian)
24. Oaks A.W., Marsh-Armstrong N., Jones J.M., Credle J.J., Sidhu A. Synucleins antagonize endoplasmic reticulum function to modulate dopamine transporter trafficking. PLoS One. 2013; 8(8): e70872. doi: 10.1371/journal.pone.0070872.
Published
2020-11-26
How to Cite
Pavlenko T., Kukharsky . M., Grigoryev A., Struchkova S., Beznos O., Chesnokova N. Experimental justification for the possibility of prediction of the development of neurodegenerative diseases following gamma-sinuclein dysfunction based on the influence of dopaminergic system on the intraocular pressure. // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2020. VOL. 64. № 4. PP. 5–11.
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Original research
