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The Journal of Neuroscience, June 8, 2005, 25(23):5544-5552; doi:10.1523/JNEUROSCI.0482-05.2005

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Neurobiology of Disease
-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells

Wanli W. Smith,¹ Russell L. Margolis,¹ Xiaojie Li,^2,6 Juan C. Troncoso,³ Michael K. Lee,³ Valina L. Dawson,^2,4,5,6 Ted M. Dawson,^2,4,6 Takashi Iwatsubo,⁷ and Christopher A. Ross^1,2,4

Departments of ¹Psychiatry, ²Neurology, ³Pathology, ⁴Neuroscience, and ⁵Physiology, and ⁶Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ⁷Department of Neuropathology and Neuroscience, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Previous reports have shown that -synuclein deposited in brain tissue from individuals with synucleinopathy is extensively phosphorylated at Ser-129. Here, we investigate the role of phosphorylation of -synuclein in the formation of inclusions involving synphilin-1 and parkin using site-directed mutagenesis to change Ser-129 of -synuclein to alanine (S129A) to abolish phosphorylation at this site. Coexpression of wild-type -synuclein and synphilin-1 in human neuroblastoma SH-SY5Y cells yielded cytoplasmic eosinophilic inclusions with some features resembling Lewy bodies, whereas coexpression of S129A -synuclein and synphlin-1 formed few or no inclusions. Moreover, coexpression of parkin with -synuclein and synphilin-1 formed more ubiquitinated inclusions, but these inclusions decreased with expression of S129A -synuclein instead of wild-type -synuclein. Coimmunoprecipitation assays revealed a decreased interaction of S129A -synuclein with synphilin-1 compared with wild-type -synuclein. Expression of S129A -synuclein instead of wild-type -synuclein also decreased the association of synphilin-1 and parkin and subsequently reduced the parkin-mediated ubiquitination of synphilin-1 and the formation of ubiquitinated inclusions. Treatment of SH-SY5Y cells with H₂O₂ increased -synuclein phosphorylation and enhanced the formation of inclusions formed by coexpression of -synuclein, synphilin-1, and parkin, whereas treatment with the casein kinase 2 inhibitor 5,6-dichloro-1--D-ribofuranosylbenzimidazole had the opposite affect. These results indicate that phosphorylation of -synuclein at S129 may be important for the formation of inclusions in PD and related synucleinopathies.

Key words: -synuclein; Parkinson's disease; synphilin-1; parkin; ubiquitin; eosinophilic inclusion; Lewy body

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Received June 3, 2004; revised April 26, 2005; accepted May 1, 2005.

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