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First published online March 2, 2004
doi: 10.1242/10.1242/jcs.00967

Journal of Cell Science 117, 1017-1024 (2004)
Published by The Company of Biologists 2004
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Research Article

Parkinson's disease {alpha}-synuclein mutations exhibit defective axonal transport in cultured neurons

Anirban R. Saha1,*, Josephine Hill1,*, Michelle A. Utton1, Ayodeji A. Asuni1, Steven Ackerley1, Andrew J. Grierson1, Christopher C. Miller1, Alun M. Davies2, Vladimir L. Buchman2, Brian H. Anderton1 and Diane P. Hanger1,{ddagger}

1 Department of Neuroscience, PO Box 38, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK
2 Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, Edinburgh, EH9 1QH, UK

{ddagger} Author for correspondence (e-mail: d.hanger{at}iop.kcl.ac.uk)

Accepted 4 November 2003

{alpha}-Synuclein is a major protein constituent of Lewy bodies and mutations in {alpha}-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation of perikaryal and neuritic aggregates of {alpha}-synuclein, which is a presynaptic protein, is that the mutations disrupt {alpha}-synuclein transport and lead to its proximal accumulation. We found that mutant forms of {alpha}-synuclein, either associated with Parkinson's disease (A30P or A53T) or mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal transport following transfection into cultured neurons. Furthermore, transfection of A30P, but not wild-type, {alpha}-synuclein results in accumulation of the protein proximal to the cell body. We propose that the reduced axonal transport exhibited by the Parkinson's disease-associated {alpha}-synuclein mutants examined in this study might contribute to perikaryal accumulation of {alpha}-synuclein and hence Lewy body formation and neuritic abnormalities in diseased brain.

Key words: Synuclein, Axonal transport, Lewy body, Parkinson's disease, Aggregation, Neurodegeneration




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© The Company of Biologists Ltd 2004