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J. Biol. Chem., Vol. 281, Issue 1, 334-340, January 6, 2006

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Familial Parkinson Mutant -Synuclein Causes Dopamine Neuron Dysfunction in Transgenic Caenorhabditis elegans^*

Tomoki Kuwahara1, Akihiko Koyama1, Keiko Gengyo-Ando, Mayumi Masuda¶, Hisatomo Kowa, Makoto Tsunoda¶, Shohei Mitani, and Takeshi Iwatsubo2

From the Departments of Neuropathology and Neuroscience and ^¶Bioanalytical Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan and Department of Physiology, School of Medicine, Tokyo Women's Medical University, Tokyo, 162-8666 Japan

Mutations in -synuclein gene cause familial form of Parkinson disease, and deposition of wild-type -synuclein as Lewy bodies occurs as a hallmark lesion of sporadic Parkinson disease and dementia with Lewy bodies, implicating -synuclein in the pathogenesis of Parkinson disease and related neurodegenerative diseases. Dopamine neurons in substantia nigra are the major site of neurodegeneration associated with -synuclein deposition in Parkinson disease. Here we establish transgenic Caenorhabditis elegans (TG worms) that overexpresses wild-type or familial Parkinson mutant human -synuclein in dopamine neurons. The TG worms exhibit accumulation of -synuclein in the cell bodies and neurites of dopamine neurons, and EGFP labeling of dendrites is often diminished in TG worms expressing familial Parkinson disease-linked A30P or A53T mutant -synuclein, without overt loss of neuronal cell bodies. Notably, TG worms expressing A30P or A53T mutant -synuclein show failure in modulation of locomotory rate in response to food, which has been attributed to the function of dopamine neurons. This behavioral abnormality was accompanied by a reduction in neuronal dopamine content and was treatable by administration of dopamine. These phenotypes were not seen upon expression of -synuclein. The present TG worms exhibit dopamine neuron-specific dysfunction caused by accumulation of -synuclein, which would be relevant to the genetic and compound screenings aiming at the elucidation of pathological cascade and therapeutic strategies for Parkinson disease.

Received for publication, May 3, 2005 , and in revised form, October 25, 2005.

^* This work was supported by the Ministry of Education, Science, Culture and Sports on Priority Areas-Advanced Brain Science Project and for the Special 21st Century Center of Excellence Program and by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyoku Tokyo, 113-0033 Japan. Tel.: 81-3-5841-4877; Fax: 81-3-5841-4708; E-mail: iwatsubo{at}mol.f.u-tokyo.ac.jp.

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