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

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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.

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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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Acknowledgments

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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Authors and Affiliations

  1. Department of Neurology, Saint Louis VAMC and Saint Louis University Health Sciences Center, St Louis, MO, 63125, USA

    William J. Burke, Shu Wen Li & Yi Pan

  2. Department of Medicine, Saint Louis VAMC and Saint Louis University Health Sciences Center, St Louis, MO, 63125, USA

    William J. Burke, Vijaya B. Kumar & Mark W. Franko

  3. Division of Geriatric Research, VA Medical Center, St Louis, MO, 63125, USA

    Vijaya B. Kumar

  4. Department of Neurology, Anatomy and Neurobiology, Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, 63110, USA

    Neeraj Pandey, Mark O’Dell & James E. Galvin

  5. Department of Pharmacological and Physiological Sciences, Saint Louis VAMC and Saint Louis University Health Sciences Center, St Louis, MO, 63125, USA

    W. Michael Panneton & Qi Gan

  6. Department of Pathology, Saint Louis VAMC and Saint Louis University Health Sciences Center, St Louis, MO, 63125, USA

    Hyung D. Chung

  7. Jefferson Barracks VAMC, #1 Jefferson Barracks Drive, St Louis, MO, 63125, USA

    Vijaya B. Kumar

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  1. William J. Burke
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  11. James E. Galvin
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Correspondence to Vijaya B. Kumar.

Additional information

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).

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Burke, W.J., Kumar, V.B., Pandey, N. et al. Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol 115, 193–203 (2008). https://doi.org/10.1007/s00401-007-0303-9

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  • DOI: https://doi.org/10.1007/s00401-007-0303-9

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