BRIEF COMMUNICATION Lack of Nigral Pathology in Transgenic Mice Expressing Human -Synuclein Driven by the Tyrosine Hydroxylase Promoter Yasuji Matsuoka, 1 Miquel Vila,* ,1 Sarah Lincoln, † Alison McCormack, ‡ Melanie Picciano, John LaFrancois, Xin Yu, † , Dennis Dickson, † William J. Langston, ‡ Eileen McGowan, † Matt Farrer, † John Hardy, † Karen Duff, Serge Przedborski,* and Donato A. Di Monte ‡ Dementia Research Group, Nathan Kline Institute/New York University Medical School, 140 Old Orangeburg Road, Orangeburg, New York 10962; *Department of Neurology and Pathology, Columbia University, 650 West 168th Street, New York, New York 10032; † Mayo Clinic Jacksonville, Birdsall Building, 4500 San Pablo Road, Jacksonville, Florida 32224; and ‡ The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, California 94089 Received July 26, 2000; revised January 12, 2001; accepted February 12, 2001; published online May 3, 2001 -Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson’s disease. Mutations in -synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human -synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human -synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human -synuclein accumulated in dopaminergic cell bodies, Lewy-type- positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of -synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes. © 2001 Academic Press INTRODUCTION The potential role of -synuclein in the pathophys- iology of Parkinson’s disease has attracted a great deal of attention as mutations in the -synuclein gene have been found to be responsible for rare, familial cases of Parkinsonism (Polymeropoulos et al., 1997; Kruger et al., 1998). Abnormal -synuclein has been identified as a major component of Lewy bodies, one of the patho- logic hallmarks of Parkinson’s disease (Spillantini et al., 1998). Lewy body inclusions are prominent in neu- rons of the substantia nigra and in addition to -synuclein fibrils, they also include ubiquitin, neuro- filaments, and a range of other proteins (reviewed in Braak and Braak, 2000). In a recent study, mice ex- pressing a wild-type (wt) human -synuclein trans- gene driven by the platelet-derived growth factor (PDGF) promoter were reported to develop -synuclein and ubiquitin immunoreactive inclusions that were argyrophilic and positive for thioflavin S. Although nigral cell body numbers were normal, there was evidence of damage to striatal dopaminergic ter- 1 These authors contributed equally to this work. Neurobiology of Disease 8, 535–539 (2001) doi:10.1006/nbdi.2001.0392, available online at http://www.idealibrary.com on 0969-9961/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved. 535