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In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity

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Summary

α-Synuclein (αSYN) plays a central role in the neural degeneration of Parkinson’s disease (PD) through its conformational change. In PD, αSYN, released from the membrane, accumulates in the cytoplasm and forms Lewy body. However, the mechanism behind the translocation and conformational change of αSYN leading to the cell death has not been well elucidated. This paper reports that in the dopamine neurons of the substantia nigra containing neuromelanin from PD patients, αSYN was modified with acrolein (ACR), an aldehyde product of lipid peroxidation. Histopathological observation confirmed the co-localization of protein immunoreactive to anti-αSYN and ACR antibody. By Western blot analyses of samples precipitated with either anti-αSYN or anti-ACR antibody, increase in ACR-modified αSYN was confirmed in PD brain. Modification of recombinant αSYN by ACR enhanced its oligomerization, and at higher ACR concentrations αSYN was fragmented and polymerized forming a smear pattern in SDS-PAGE. ACR reduced 20S proteasome activity through the direct modification of the proteasome proteins and the production of polymerized ACR-modified proteins, which inhibited proteasome activity in vitro. These results suggest that ACR may initiate vicious cycle of modification and aggregation of proteins, including αSYN, and impaired proteolysis system, to cause neuronal death in PD.

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Abbreviations

ACR:

acrolein

αSYN:

α-synuclein

HNE:

4-hydroxy-2-nonenal

PD:

Parkinson’s disease

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

UPS:

ubiquitin-proteasome system

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Authors and Affiliations

  1. National Center for Geriatrics and Gerontology, Department of Geriatric Medicine, Obu, Aichi, Japan

    M. Shamoto-Nagai & W. Maruyama

  2. Institute for Medical Science of Ageing, Aichi Medical University, Nagakute-cho, Aichi, Japan

    Y. Hashizume & M. Yoshida

  3. Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya, Aichi, Japan

    T. Osawa

  4. Clinical Neurochemistry and NPF Center of Excellence Laboratories, Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    P. Riederer

  5. Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan

    M. Naoi

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  1. M. Shamoto-Nagai
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  2. W. Maruyama
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  3. Y. Hashizume
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  4. M. Yoshida
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  5. T. Osawa
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  6. P. Riederer
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  7. M. Naoi
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Shamoto-Nagai, M., Maruyama, W., Hashizume, Y. et al. In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity. J Neural Transm 114, 1559–1567 (2007). https://doi.org/10.1007/s00702-007-0789-2

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