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The Journal of Neuroscience, March 21, 2007, 27(12):3338-3346; doi:10.1523/JNEUROSCI.0285-07.2007

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Neurobiology of Disease
Aggregated -Synuclein Mediates Dopaminergic Neurotoxicity In Vivo

Magali Periquet,¹ Tudor Fulga,¹ Liisa Myllykangas,¹ Michael G. Schlossmacher,² and Mel B. Feany¹

¹Department of Pathology and ²Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Mel B. Feany, Department of Pathology, New Research Building, Room 630, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: mel_feany{at}hms.harvard.edu

Mutations in the synaptic protein -synuclein cause rare genetic forms of Parkinson's disease. -Synuclein is thought to play a critical role in more common sporadic cases of Parkinson's disease as well because the protein aggregates in the hallmark intraneuronal inclusions of the disorder, Lewy bodies. To test the role of protein aggregation in the pathogenesis of Parkinson's disease, we expressed a form of -synuclein with a deletion of amino acids 71–82 that is unable to aggregate in vitro in a transgenic Drosophila model of the disorder. We found no evidence of large aggregates or oligomeric species of -synuclein in these animals and no loss of tyrosine hydroxylase-positive neurons. We also expressed a truncated form of -synuclein that has enhanced ability to aggregate in vitro. This truncated form of -synuclein showed increased aggregation into large inclusions bodies, increased accumulation of high molecular weight -synuclein species, and demonstrated enhanced neurotoxicity in vivo. Our findings thus support a critical role for aggregation of -synuclein in mediating toxicity to dopaminergic neurons in vivo, although the precise role each aggregated form of -synuclein plays in neurotoxicity remains to be determined.

Key words: Parkinson's; Drosophila; -synuclein; aggregation; dopaminergic; C-terminal truncation

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Received June 1, 2006; accepted Feb. 18, 2007.

Correspondence should be addressed to Mel B. Feany, Department of Pathology, New Research Building, Room 630, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: mel_feany{at}hms.harvard.edu

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