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Glycobiology Advance Access originally published online on July 21, 2005
Glycobiology 2005 15(12):1320-1331; doi:10.1093/glycob/cwj014
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Agrin binds {alpha}-synuclein and modulates {alpha}-synuclein fibrillation

I-Hsuan Liu2, Vladimir N. Uversky3, Larissa A. Munishkina3, Anthony L. Fink3, Willi Halfter4 and Gregory J. Cole1,2

2 Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707; 3 Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064; and 4 Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261

1 To whom correspondence should be addressed; e-mail: gcole{at}nccu.edu

Received on May 2, 2005; revised on June 28, 2005; accepted on July 11, 2005

Recent studies have begun to investigate the role of agrin in brain and suggest that agrin’s function likely extends beyond that of a synaptogenic protein. Particularly, it has been shown that agrin is associated with the pathological lesions of Alzheimer’s disease (AD) and may contribute to the formation of ß-amyloid (Aß) plaques in AD. We have extended the analysis of agrin’s function in neurodegenerative diseases to investigate its role in Parkinson’s disease (PD). {alpha}-Synuclein is a critical molecular determinant in familial and sporadic PD, with the formation of {alpha}-synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to {alpha}-synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by ß-sheet structure, and enhances insolubility of {alpha}-synuclein. We also show that agrin accelerates the formation of protofibrils by {alpha}-synuclein and decreases the half-time of fibril formation. The association of agrin with PD lesions was also explored in PD human brain, and these studies shown that agrin colocalizes with {alpha}-synuclein in neuronal Lewy bodies in the substantia nigra of PD brain. These studies indicate that agrin is capable of accelerating the formation of insoluble protein fibrils in a second common neurodegenerative disease. These findings may indicate shared molecular mechanisms leading to the pathophysiology in these two neurodegenerative disorders.

Key words: agrin / heparan sulfate proteoglycan / Parkinson’s disease / protein conformational disorders / {alpha}-synuclein


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