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The Journal of Neuroscience, October 15, 2001, 21(20):8053-8061

Induction of -Synuclein Aggregation by Intracellular Nitrative Insult

Evgenia Paxinou¹, Qiping Chen¹, Marie Weisse¹, Benoit I. Giasson², Erin H. Norris², Susan M. Rueter², John Q. Trojanowski², Virginia M.-Y. Lee², and Harry Ischiropoulos¹

¹ Stokes Research Institute and Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania 19104, and ² Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania 19104

Brain lesions containing filamentous and aggregated -synuclein are hallmarks of neurodegenerative synucleinopathies. Oxidative stress has been implicated in the formation of these lesions. Using HEK 293 cells stably transfected with wild-type and mutant -synuclein, we demonstrated that intracellular generation of nitrating agents results in the formation of -synuclein aggregates. Cells were exposed simultaneously to nitric oxide- and superoxide-generating compounds, and the intracellular formation of peroxynitrite was demonstrated by monitoring the oxidation of dihydrorhodamine 123 and the nitration of -synuclein. Light microscopy using antibodies against -synuclein and electron microscopy revealed the presence of perinuclear aggregates under conditions in which peroxynitrite was generated but not when cells were exposed to nitric oxide- or superoxide-generating compounds separately. -Synuclein aggregates were observed in 20-30% of cells expressing wild-type or A53T mutant -synuclein and in 5% of cells expressing A30P mutant -synuclein. No evidence of synuclein aggregation was observed in untransfected cells or cells expressing -synuclein. In contrast, selective inhibition of the proteasome resulted in the formation of aggregates detected with antibodies to ubiquitin in the majority of the untransfected cells and cells expressing -synuclein. However, -synuclein did not colocalize with these aggregates, indicating that inhibition of the proteasome does not promote -synuclein aggregation. In addition, proteasome inhibition did not alter the steady-state levels of -synuclein, but addition of the lysosomotropic agent ammonium chloride significantly increased the amount of -synuclein, indicating that lysosomes are involved in degradation of -synuclein. Our data indicate that nitrative and oxidative insult may initiate pathogenesis of -synuclein aggregates.

Key words: superoxide; nitric oxide; peroxynitrite; -synuclein aggregation; ubiquitin; proteasome; Parkinson's disease.

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21208053-09$05.00/0

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