Acta Neuropathologica

, Volume 115, Issue 2, pp 193–203 | Cite as

Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine

  • William J. Burke
  • Vijaya B. KumarEmail author
  • Neeraj Pandey
  • W. Michael Panneton
  • Qi Gan
  • Mark W. Franko
  • Mark O’Dell
  • Shu Wen Li
  • Yi Pan
  • Hyung D. Chung
  • James E. Galvin
Original Paper


Parkinson’s disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons and the presence of α-synuclein (AS) aggregates as Lewy bodies (LBs) in the remaining substantia nigra (SN) neurons. A continuing puzzle in studying PD pathogenesis is that although AS is expressed throughout the brain, LBs and selective dopaminergic cell loss lead to characteristic clinical signs of PD, suggesting that there is a link between AS aggregation and DA metabolism. One potential candidate for this link is the monoamine oxidase (MAO) metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as neither DA nor DA metabolites other than DOPAL are toxic to SN neurons at physiological concentrations. We tested DOPAL-induced AS aggregation in a cell-free system, in vitro in DA neuron cultures and in vivo with stereotactic injections into the SN of Sprague–Dawley rats by Western blots, fluorescent confocal microscopy and immunohistochemistry. We demonstrate that DOPAL in physiologically relevant concentrations, triggers AS aggregation in the cell-free system, and in cell cultures resulting in the formation of potentially toxic AS oligomers and aggregates. Furthermore, DOPAL injection into the SN of Sprague–Dawley rats resulted in DA neuron loss and the accumulation of high molecular weight oligomers of AS detected by Western blot. Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD.


Parkinson’s disease α-Synuclein 3,4-Dihydroxyphenylacetaldehyde Dopamine metabolite 



Parkinson’s disease




Dopamine quinone






Lewy bodies


Monamine oxidase


Mitochondrial permeability transition pore




Substantia nigra


Polyvinilidene difluoride


Tris buffered saline


Polymerase chain reaction


SHSY-5Y cells


Enhanced chemiluminescence


Tyrosine hydroxylase


Diamonobenzidine dichloride


3,4-Dihydroxyphenylacetic acid


Homovanillic acid


Wild type




Dopamine transporter


Aldehyde dehydrogenase


Polyacrylamide gel electrophoresis


Ventral tegmental area



The authors are grateful for the help of Prof. Vijaya Lakshmi and Mrs. Priscilla Dehaven in some of the experiments. They also thank Dr. John Trojanowski for the AS 202 antibody. This study was supported by grants from Missouri ADRDA Program (WJB, NP), Nestle Foundation (VBK), St Louis VAMC (WJB,VBK), NIH HL 64772 (WMP), NIH AG20764, AG 03991, AG 05681 (JEG), the American Federation on Aging Research (JEG), and generous gifts from the Alan A. and Edith L. Wolff Charitable Trust (JEG) and Blue Gator Foundation (JEG). Dr. Galvin is a recipient of the Paul Beeson Physician Faculty Scholar Award in Aging Research and the American Academy of Neurology Research Award in Geriatric Neurology.


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • William J. Burke
    • 1
    • 2
  • Vijaya B. Kumar
    • 2
    • 3
    • 7
    Email author
  • Neeraj Pandey
    • 4
  • W. Michael Panneton
    • 5
  • Qi Gan
    • 5
  • Mark W. Franko
    • 2
  • Mark O’Dell
    • 4
  • Shu Wen Li
    • 1
  • Yi Pan
    • 1
  • Hyung D. Chung
    • 6
  • James E. Galvin
    • 4
  1. 1.Department of NeurologySaint Louis VAMC and Saint Louis University Health Sciences CenterSt LouisUSA
  2. 2.Department of MedicineSaint Louis VAMC and Saint Louis University Health Sciences CenterSt LouisUSA
  3. 3.Division of Geriatric ResearchVA Medical CenterSt LouisUSA
  4. 4.Department of Neurology, Anatomy and Neurobiology, Alzheimer’s Disease Research CenterWashington University School of MedicineSt LouisUSA
  5. 5.Department of Pharmacological and Physiological SciencesSaint Louis VAMC and Saint Louis University Health Sciences CenterSt LouisUSA
  6. 6.Department of PathologySaint Louis VAMC and Saint Louis University Health Sciences CenterSt LouisUSA
  7. 7.Jefferson Barracks VAMCSt LouisUSA

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