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. Kumar
  • 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

Abstract

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.

Keywords

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

Abbreviations

PD

Parkinson’s disease

DA

Dopamine

DAQ

Dopamine quinone

CA

Catecholamine

AS

α-synuclein

LB

Lewy bodies

MAO

Monamine oxidase

mPTP

Mitochondrial permeability transition pore

DOPAL

3,4-Dihydroxyphenylacetaldehyde

SN

Substantia nigra

PVDF

Polyvinilidene difluoride

TBS

Tris buffered saline

PCR

Polymerase chain reaction

5Y

SHSY-5Y cells

ECL

Enhanced chemiluminescence

TH

Tyrosine hydroxylase

DAB

Diamonobenzidine dichloride

DOPAC

3,4-Dihydroxyphenylacetic acid

HVA

Homovanillic acid

WT

Wild type

IR

Immunoreactivity

DAT

Dopamine transporter

ALDH

Aldehyde dehydrogenase

PAGE

Polyacrylamide gel electrophoresis

VTA

Ventral tegmental area

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • William J. Burke
    • 1
    • 2
  • Vijaya B. Kumar
    • 2
    • 3
    • 7
  • 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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