Gene Expression of Lysosomal Membrane Proteins in Parkinson Disease, Associated with Mutations in the Glucocerebrosidase Gene (GBA)

Cover Page

Abstract

Introduction. In carriers of a mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene, the risk of Parkinson disease (PD) is increased by 7–8 times. However, not all carriers of the GBA gene mutations develop PD during their lifetime. We hypothesize that the dysfunction in the lysosomal membrane proteins involved in autophagy and transport of GBA into the lysosomes can contribute to the development of PD in carriers of mutations in the GBA gene.

The aim of the study was to assess the contribution of LAMP2 and SCARB2 genes expression in CD45+ peripheral blood cells to the development of GBA-PD.

Materials and methods. We examined 9 patients with GBA-PD, 9 asymptomatic GBA gene mutations carriers, 37 patients with PD, and 56 people in the control group. The relative mRNA level of LAMP2 and SCARB2 genes in CD45+ blood cells, obtained using magnetic sorting, was measured by quantitative real-time polymerase chain reaction using fluorescent probes.

Results. The relative mRNA level of LAMP2 and SCARB2 genes in CD45+ blood cells was reduced in patients with GBA-PD in comparison to patients with PD and to controls (LAMP2: p<0.0001, p = 0.01 respectively; SCARB2: p = 0.01, p<0.05, respectively) and in asymptomatic carriers of GBA gene mutations compared to patients with PD (LAMP2: p = 0.021; SCARB2: p<0.05) and controls (LAMP2: p = 0.029). We also found decreased mRNA levels of the LAMP2 gene (p = 0.024) and the absence of differences in the mRNA levels of the SCARB2 gene (р<0.05) in CD45+ blood cells in patients with GBA-PD when compared to the group of asymptomatic carriers of GBA gene mutations.

Conclusion. GBA-PD is characterized by a pronounced expression of the LAMP2 gene in the CD45+ peripheral blood cells, which may indicate a role of the decreased LAMP2 gene expression in the pathogenesis of GBA-PD.

About the authors

Tatiana S. Usenko

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

Anastasia I. Bezrukova

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

Darya A. Bogdanova

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

Mikhail A. Nikolaev

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

Irina V. Miliukhina

Institute of Experimental Medicine, Saint-Petersburg

Email: platonova@neurology.ru
Russian Federation

Elizaveta V. Gracheva

Institute of Experimental Medicine, Saint-Petersburg

Email: platonova@neurology.ru
Russian Federation

Konstantin A. Senkevich

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

Ekaterina Yu. Zakharova

Research Centre for Medical Genetics, Moscow

Email: platonova@neurology.ru
Russian Federation

Anton K. Emelyanov

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

Sofya N. Pchelina

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina

Email: platonova@neurology.ru
Russian Federation

References

  1. Lepori L.R. [Parkinson's disease. Miniatlas]. Moscow, 2011. (in Russ.).
  2. Emelyanov A.K., Usenko T.S., Tesson C. et al. Mutation analysis of Parkinson's disease genes in a Russian data set. Neurobiol Aging 2017; 71: 267.e7-267.e10. doi: 10.1016/j.neurobiolaging.2018.06.027. PMID: 30146349.
  3. O'Regan G., deSouza R.M., Balestrino R., Schapira A.H. Glucocerebrosidase mutations in Parkinson disease. J Parkinsons Dis 2017; 7: 411–422. doi: 10.3233/JPD-171092. PMID: 28598856.
  4. Schapira A.H. Glucocerebrosidase and Parkinson disease: recent advances. Mol Cell Neurosci 2015; 66: 37–42. doi: 10.1016/j.mcn.2015.03.013. PMID: 25802027.
  5. Chen X., Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation 2008; 117: 3171–3180. doi: 10.1161/CIRCULATIONAHA.107.730366. PMID: 18559702.
  6. Klein A.D., Mazzulli J.R. Is Parkinson's disease a lysosomal disorder? Brain 2018; 141: 2255–2262. doi: 10.1093/brain/awy147. PMID: 29860491.
  7. Robak L.A., Jansen I.E., van Rooij J. et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain 2017; 140: 3193–3203. doi: 10.1093/brain/awx285. PMID: 29140481.
  8. Senkevich K.A., Miliukhina I.V., Beletskaia M.V. et al. [The clinical features of Parkinson's disease in patients with mutations and polymorphic variants of GBA gene]. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova 2017; 117(10): 81–86. doi: 10.17116/jnevro201711710181-86. PMID: 29171494.
  9. Aharon-Peretz J., Rosenbaum H., Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi jews. N Engl J Med 2004; 351: 1972–1977. doi: 10.1056/NEJMoa033277. PMID: 15525722.
  10. Siebert M., Bock H., Michelin-Tirelli K. et al. Novel mutations in the glucocerebrosidase gene of brazilian patients with Gaucher disease. JIMD Rep 2013; 9: 7–16. doi: 10.1007/8904_2012_174. PMID: 23430543.
  11. Livak K., Schmittgen T. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408. doi: 10.1006/meth.2001.1262. PMID: 11846609.
  12. Alcalay R.N., Levy O.A., Waters C.C. et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain 2015; 138: 2648–2658. doi: 10.1093/brain/awv179. PMID: 26117366.
  13. Pchelina S., Emelyanov A., Baydakova G. et al. Oligomeric α-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson's disease. Neurosci Lett 2017; 636: 70–76. doi: 10.1016/j.neulet.2016.10.039. PMID: 27780739.
  14. Guedes L.C., Chan R.B., Gomes M.A. et al. Serum lipid alterations in GBA-associated Parkinson's disease. Parkinsonism Relat Disord 2017; 44: 58–65. doi: 10.1016/j.parkreldis.2017.08.026. PMID: 28890071.
  15. Pchelina S., Baydakova G., Nikolaev M. et al. Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations. Mov Disord 2018; 33: 1325–1330. doi: 10.1002/mds.27393. PMID: 30192031.
  16. Nuzhnyi E., Emelyanov A., Boukina T. et al. Plasma oligomeric alpha-synuclein is associated with glucocerebrosidase activity in Gaucher disease. Mov Disord 2015; 30: 989–991. doi: 10.1002/mds.26200. PMID: 25962734.
  17. Cuervo A.M., Stefanis L., Fredenburg R. et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004; 305: 1292–1295. doi: 10.1126/science.1101738. PMID: 15333840.
  18. Vogiatzi T., Xilouri M., Vekrellis K., Stefanis L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 2008; 283: 23542–23556. doi: 10.1074/jbc.M801992200. PMID: 18566453.
  19. Sala G., Marinig D., Arosio A., Ferrarese C. Role of chaperone-mediated autophagy dysfunctions in the pathogenesis of Parkinson's disease. Front Mol Neurosci 2016; 9: 157. doi: 10.3389/fnmol.2016.00157. PMID: 28066181.
  20. Mazzulli J.R., Xu Y.H., Sun Y. et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011; 146: 37–52. doi: 10.1016/j.cell.2011.06.001. PMID: 21700325.
  21. Mazzulli J.R., Zunke F., Isacson O. et al. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci USA 2016; 113: 1931–1936. doi: 10.1073/pnas.1520335113. PMID: 26839413.
  22. Ortega R.A., Torres P.A., Swan M. et al. Glucocerebrosidase enzyme activity in GBA mutation Parkinson's disease. J Clin Neurosci 2016; 28: 185–186. doi: 10.1016/j.jocn.2015.12.004. PMID: 26857292.
  23. Choi J.H., Stubblefield B., Cookson M.R. et al. Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab 2011; 104: 185–188. doi: 10.1016/j.ymgme.2011.06.008. PMID: 21742527.
  24. Cerri S., Blandini F. Role of autophagy in Parkinson's disease. Curr Med Chem 2019; 26: 3702–3718. doi: 10.2174/0929867325666180226094351. PMID: 29484979.
  25. Gonzalez A., Valeiras M., Sidransky E., Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014; 111: 84–91. doi: 10.1016/j.ymgme.2013.12.005. PMID: 24389070.
  26. Alcalay R.N., Levy O.A., Wolf P. et al. SCARB2 variants and glucocerebrosidase activity in Parkinson's disease. NPJ Parkinsons Dis 2016; 2. pii: 1600. doi: 10.1038/npjparkd.2016.4. PMID: 27110593.
  27. Velayati A., DePaolo J., Gupta N. et al. A mutation in SCARB2 is a modifier in Gaucher disease. Hum Mutat 2011; 32: 1232–1238. doi: 10.1002/humu.21566. PMID: 21796727.
  28. Liou B., Haffey W.D., Greis K.D., Grabowski G.A. The LIMP-2/SCARB2 binding motif on acid β-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases. J Biol Chem 2014; 289: 30063–30074. doi: 10.1074/jbc.M114.593616. PMID: 25202012.
  29. Gan-Or Z., Dion P.A., Rouleau G.A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 2015; 11: 1443–1457. doi: 10.1080/15548627.2015.1067364. PMID: 26207393.
  30. Moors T.E., Paciotti S., Ingrassia A. et al. Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson's disease and dementia with Lewy bodies. Mol Neurobiol 2019; 56: 1344–1355. doi: 10.1007/s12035-018-1090-0. PMID: 29948939.
  31. Rudenok M.M., Alieva A.Kh., Nikolaev M.A. et al. Possible involvement of genes related to lysosomal storage disorders in the pathogenesis of Parkinson's disease. Mol Biol 2019; 53(1):81-86. doi: 10.1134/s0026898419010142.
  32. Murphy K.E., Gysbers A.M., Abbott S.K. et al. Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease. Mov Disord 2015; 30: 1639–1647. doi: 10.1002/mds.26141. PMID: 25594542.
  33. Alvarez-Erviti L., Rodriguez-Oroz M.C., Cooper J.M. et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 2010; 67: 1464–1472. doi: 10.1001/archneurol.2010.198. PMID: 20697033.
  34. Wu G., Wang X., Feng X. et al. Altered expression of autophagic genes in the peripheral leukocytes of patients with sporadic Parkinson's disease. Brain Res 2011; 1394: 105–111. doi: 10.1016/j.brainres.2011.04.013. PMID: 21514572.
  35. Kim H.J., Jeon B., Song J. et al. Leukocyte glucocerebrosidase and β-hexosaminidase activity in sporadic and genetic Parkinson disease. Parkinsonism Relat Disord 2016; 23: 99–101. doi: 10.1016/j.parkreldis.2015.12.002. PMID: 26705847.

Statistics

Views

Abstract: 411

PDF (Russian): 291

Article Metrics

Metrics Loading ...

Dimensions

PlumX


Copyright (c) 2020 Usenko T.S., Bezrukova A.I., Bogdanova D.A., Nikolaev M.A., Miliukhina I.V., Gracheva E.V., Senkevich K.A., Zakharova E.Y., Emelyanov A.K., Pchelina S.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies