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Vol. 10, No. 1-4, 2012
Issue release date: April 2012
Section title: Paper
Open Access Gateway
Neurodegenerative Dis 2012;10:203–206
(DOI:10.1159/000332598)

Exon Arrays Reveal Alternative Splicing Aberrations in Parkinson’s Disease Leukocytes

Soreq L.a · Bergman H.a, c, d · Israel Z.d · Soreq H.b, c
aDepartment of Medical Neurobiology, Hebrew University-Hadassah Faculty of Medicine, bDepartment of Biological Chemistry, The Life Sciences Institute, and cThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, and dCenter for Functional and Restorative Neurosurgery, Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel
email Corresponding Author

Abstract

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease worldwide. Clinical diagnosis can only be made when the vast majority of the dopaminergic cell population has died. However, the cause(s) for sporadic PD is/are yet unclear. Transcript changes have recently been described in PD patients’ whole blood cells, but corresponding splicing patterns remained unknown. Objective: To search for alternative splicing aberrations in PD patients’ blood leukocytes. Methods: We applied exon microarrays to profile PD patients’ blood leukocyte mRNA. Exon level splicing analysis served as a basis for downstream classification and functional analyses. Results: Patients and carefully matched controls were classified by the splicing exon profiles of their leukocyte transcripts. Specifically, many exons were downregulated in PD patients compared to controls. Functional analysis highlighted aberrant splicing of PD-related transcripts and impaired NF-ĸB cascade and immune response. Conclusion: PD patient’s blood leukocytes exhibit alternative splicing of numerous transcripts. The aberrant alternative splicing in PD patients’ blood cells has potential implications for early diagnosis and future therapeutics.

© 2011 S. Karger AG, Basel


  

Key Words

  • Alternative splicing
  • Exon microarrays
  • Leukocytes
  • Parkinson’s disease
  • Risk markers

References

  1. Nussbaum RL, Ellis CE: Alzheimer’s disease and Parkinson’s disease. N Engl J Med 2003;348:1356–1364.
  2. Braak H, Del Tredici K: Invited article: nervous system pathology in sporadic parkinson disease. Neurology 2008;70:1916.

    External Resources

  3. Tanner CM, Goldman SM: Epidemiology of Parkinson’s disease. Neurol Clin 1996;14:317–335.
  4. Fahn S: Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci 2003;991:1–14.
  5. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S: A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2–8 in the R6/2 transgenic mouse. Proc Natl Acad Sci USA 2007;104:16685–16689.
  6. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB: Alternative isoform regulation in human tissue transcriptomes. Nature 2008;456:470–476.
  7. Guo X, Chen QR, Song YK, Wei JS, Khan J: Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status. BMC Med Genomics 2011;4:35.
  8. Prinos P, Garneau D, Lucier JF, Gendron D, Couture S, Boivin M, Brosseau JP, Lapointe E, Thibault P, Durand M, Tremblay K, Gervais-Bird J, Nwilati H, Klinck R, Chabot B, Perreault JP, Wellinger RJ, Elela SA: Alternative splicing of SYK regulates mitosis and cell survival. Nat Struct Mol Biol 2011;18:673–679.
  9. Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR: Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci USA 2007;104:955–960.
  10. Soreq L, Israel Z, Bergman H, Soreq H: Advanced microarray analysis highlights modified neuro-immune signaling in nucleated blood cells from Parkinson’s disease patients. J Neuroimmunol 2008;201–202:227–236.
  11. Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995;57:289–300.
  12. Huang da W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44–57.
  13. Soreq L, Bergman H, Goll Y, Greenberg DS, Israel Z, Soreq H: Deep brain stimulation induces rapidly reversible transcript changes in Parkinson’s leukocytes. J Cell Mol Med 2011, E-pub ahead of print, 2011 Sep 12. DOI: 10.1111/j.1582-4934.2011.01444.x.

    External Resources

  

Author Contacts

Hermona Soreq, PhD
Department of Biological Chemistry
The Hebrew University of Jerusalem, The Edmond J. Safra Campus
Givat Ram, Jerusalem 91904 (Israel)
Tel. +972 2 658 5109, E-Mail soreq@cc.huji.ac.il

  

Article Information

Published online: December 9, 2011
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 1, Number of References : 13

  

Publication Details

Neurodegenerative Diseases

Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Open Access License / Drug Dosage / Disclaimer

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease worldwide. Clinical diagnosis can only be made when the vast majority of the dopaminergic cell population has died. However, the cause(s) for sporadic PD is/are yet unclear. Transcript changes have recently been described in PD patients’ whole blood cells, but corresponding splicing patterns remained unknown. Objective: To search for alternative splicing aberrations in PD patients’ blood leukocytes. Methods: We applied exon microarrays to profile PD patients’ blood leukocyte mRNA. Exon level splicing analysis served as a basis for downstream classification and functional analyses. Results: Patients and carefully matched controls were classified by the splicing exon profiles of their leukocyte transcripts. Specifically, many exons were downregulated in PD patients compared to controls. Functional analysis highlighted aberrant splicing of PD-related transcripts and impaired NF-ĸB cascade and immune response. Conclusion: PD patient’s blood leukocytes exhibit alternative splicing of numerous transcripts. The aberrant alternative splicing in PD patients’ blood cells has potential implications for early diagnosis and future therapeutics.

© 2011 S. Karger AG, Basel


  

Author Contacts

Hermona Soreq, PhD
Department of Biological Chemistry
The Hebrew University of Jerusalem, The Edmond J. Safra Campus
Givat Ram, Jerusalem 91904 (Israel)
Tel. +972 2 658 5109, E-Mail soreq@cc.huji.ac.il

  

Article Information

Published online: December 9, 2011
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 1, Number of References : 13

  

Publication Details

Neurodegenerative Diseases

Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 12/9/2011
Issue release date: April 2012

Number of Print Pages: 4
Number of Figures: 1
Number of Tables: 1

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Open Access License / Drug Dosage

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Nussbaum RL, Ellis CE: Alzheimer’s disease and Parkinson’s disease. N Engl J Med 2003;348:1356–1364.
  2. Braak H, Del Tredici K: Invited article: nervous system pathology in sporadic parkinson disease. Neurology 2008;70:1916.

    External Resources

  3. Tanner CM, Goldman SM: Epidemiology of Parkinson’s disease. Neurol Clin 1996;14:317–335.
  4. Fahn S: Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci 2003;991:1–14.
  5. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S: A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2–8 in the R6/2 transgenic mouse. Proc Natl Acad Sci USA 2007;104:16685–16689.
  6. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB: Alternative isoform regulation in human tissue transcriptomes. Nature 2008;456:470–476.
  7. Guo X, Chen QR, Song YK, Wei JS, Khan J: Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status. BMC Med Genomics 2011;4:35.
  8. Prinos P, Garneau D, Lucier JF, Gendron D, Couture S, Boivin M, Brosseau JP, Lapointe E, Thibault P, Durand M, Tremblay K, Gervais-Bird J, Nwilati H, Klinck R, Chabot B, Perreault JP, Wellinger RJ, Elela SA: Alternative splicing of SYK regulates mitosis and cell survival. Nat Struct Mol Biol 2011;18:673–679.
  9. Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR: Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci USA 2007;104:955–960.
  10. Soreq L, Israel Z, Bergman H, Soreq H: Advanced microarray analysis highlights modified neuro-immune signaling in nucleated blood cells from Parkinson’s disease patients. J Neuroimmunol 2008;201–202:227–236.
  11. Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995;57:289–300.
  12. Huang da W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44–57.
  13. Soreq L, Bergman H, Goll Y, Greenberg DS, Israel Z, Soreq H: Deep brain stimulation induces rapidly reversible transcript changes in Parkinson’s leukocytes. J Cell Mol Med 2011, E-pub ahead of print, 2011 Sep 12. DOI: 10.1111/j.1582-4934.2011.01444.x.

    External Resources