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The Journal of Neuroscience, April 12, 2006, 26(15):3942-3950; doi:10.1523/JNEUROSCI.4965-05.2006

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Neurobiology of Disease
Pathological Changes in Dopaminergic Nerve Cells of the Substantia Nigra and Olfactory Bulb in Mice Transgenic for Truncated Human -Synuclein(1–120): Implications for Lewy Body Disorders

George K. Tofaris,¹ Pablo Garcia Reitböck,¹ Trevor Humby,² Sarah L. Lambourne,² Mark O’Connell,¹ Bernardino Ghetti,³ Helen Gossage,¹ Piers C. Emson,² Lawrence S. Wilkinson,² Michel Goedert,⁴ and Maria Grazia Spillantini¹

¹Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, United Kingdom, ²The Babraham Institute, Cambridge CB2 4AT, United Kingdom, ³Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, and ⁴MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

Correspondence should be addressed to Maria Grazia Spillantini at the above address. Email: mgs11{at}cam.ac.uk

Dysfunction of the 140 aa protein -synuclein plays a central role in Lewy body disorders, including Parkinson’s disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human -synuclein(1–120), driven by the rat tyrosine hydroxylase promoter on a mouse -synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of -synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.

Key words: aggregation; behavior; tyrosine hydroxylase; fibril; dopamine; nigrostriatal; Parkinson; -synuclein

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Received June 3, 2005; revised Feb. 28, 2006; accepted March 3, 2006.

Correspondence should be addressed to Maria Grazia Spillantini at the above address. Email: mgs11{at}cam.ac.uk

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