Published online before print November 30, 2007

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2007.070373v1 171/6/2000    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Assayag, K. Articles by Sharon, R. Search for Related Content PubMed PubMed Citation Articles by Assayag, K. Articles by Sharon, R.

Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070373

Accepted for publication September 11, 2007.

Article

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

^@ To whom correspondence should be addressed. E-mail: rsharon{at}md.huji.ac.il.

	Abstract

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.