Published online before print November 30, 2007

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(American Journal of Pathology. 2007;171:2000-2011.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070373

Polyunsaturated Fatty Acids Induce -Synuclein-Related Pathogenic Changes in Neuronal Cells

Karen Assayag^*, Evgenia Yakunin^*, Virginie Loeb^*, Dennis J. Selkoe and Ronit Sharon^*

From the Department of Cellular Biochemistry and Human Genetics,^* Hebrew University, Hadassah Medical School, Jerusalem, Israel; and the Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

The misfolding and aggregation of normally soluble proteins has emerged as a key feature of several neurodegenerative diseases. In Parkinson’s disease, progressive loss of dopaminergic neurons is accompanied by polymerization of the cytoplasmic protein -synuclein (S) into filamentous inclusions found in neuronal somata (Lewy bodies) and dendrites (Lewy neurites). Similar S aggregates occur in cortical neurons in dementia with Lewy bodies. Numerous reports now indicate that S can interact with lipids. We previously found that treating dopaminergic cells expressing S with polyunsaturated fatty acids (PUFAs) induced the formation of soluble, sodium dodecyl sulfate-stable oligomers whereas treatment with saturated fatty acids did not. Here, we examine the relevance of S-PUFA interactions to the development of Parkinson’s disease-like cytopathology. Exposure of S-overexpressing dopaminergic or neuronal cell lines to physiological levels of a PUFA induced the formation of proteinaceous inclusions in the cytoplasm. Kinetic experiments in-dicated that PUFA-induced soluble oligomers of S precede these Lewy-like inclusions. Importantly, we found that S oligomers were associated with cyto-toxicity, whereas the development of Lewy-like inclusions appeared to be protective. We conclude that alterations in PUFA levels can lead to aggregation of S and subsequent deposition into potentially cyto-toxic oligomers that precede inclusions in dopa-minergic cells.