Acta Neuropathologica

, Volume 121, Issue 6, pp 695–704 | Cite as

Changes in the solubility and phosphorylation of α-synuclein over the course of Parkinson’s disease

  • Jinxia Zhou
  • Melissa Broe
  • Yue Huang
  • John P. Anderson
  • Wei-Ping Gai
  • Elizabeth A. Milward
  • Michelle Porritt
  • David Howells
  • Andrew J. Hughes
  • Xiaomin Wang
  • Glenda M. Halliday
Original Paper

Abstract

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson’s disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson’s disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson’s disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson’s disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.

Keywords

Parkinson’s disease α-Synuclein Phosphorylation Solubility Disease stage 

Notes

Acknowledgments

Human brain tissue samples were received from the Australian Brain Bank Network which is supported by the National Health and Medical Research Council of Australia (NHMRC), specifically from the Sydney Brain Bank (also supported by Neuroscience Research Australia and the University of New South Wales), from the NSW Tissue Resource Centre [also supported by the Schizophrenia Research Institute, the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725, and the University of Sydney], from the South Australian Brain Bank (also supported by the Flinders Medical Centre Foundation), from the Victorian Brain Bank Network (also supported by Neurosciences Australia, the University of Melbourne, the Mental Health Research Institute of Victoria, the Alfred Hospital, and the Victorian Forensic Institute of Medicine), from the Queensland Brain Bank and from the Western Australia Brain Bank Network. This work was also supported by the NHMRC (510186) and the National Basic Research Program of China (2006CB500700), NSFC fund (30771062). Gai has a NHMRC Senior Research Fellowship 535014. Halliday has a NHMRC Senior Principal Research Fellowship 630434. We would like to thank Heather McCann for laboratory assistance and Heidi Cartwright for the preparation of the figures.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jinxia Zhou
    • 1
  • Melissa Broe
    • 1
  • Yue Huang
    • 1
  • John P. Anderson
    • 2
  • Wei-Ping Gai
    • 3
  • Elizabeth A. Milward
    • 4
  • Michelle Porritt
    • 5
  • David Howells
    • 5
  • Andrew J. Hughes
    • 5
  • Xiaomin Wang
    • 6
  • Glenda M. Halliday
    • 1
  1. 1.Neuroscience Research Australia The University of New South WalesSydneyAustralia
  2. 2.Elan Pharmaceuticals IncSouth San FranciscoUSA
  3. 3.Department of Human Physiology, The Centre for NeuroscienceFlinders University School of MedicineBedford ParkAustralia
  4. 4.School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanAustralia
  5. 5.Department of Medicine, Florey Neuroscience InstitutesThe University of MelbourneHeidelbergAustralia
  6. 6.Department of NeurobiologyKey Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical UniversityBeijingChina

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