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Glycobiology Advance Access published online on July 21, 2005
Glycobiology, 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
Received May 2, 2005
Revised June 28, 2005
Accepted July 11, 2005

Article

Agrin Binds {alpha}-Synuclein and Modulates {alpha}-Synuclein Fibrillation

I-Hsuan Liu 1, Vladimir N. Uversky 2, Larissa A. Munishkina 2, Anthony L. Fink 2, Willi Halfter 3, and Gregory J. Cole 1*

1 Department of Molecular Biomedical Sciences North Carolina State University Raleigh, NC 27606
2 Department of Chemistry and Biochemistry University of California, Santa Cruz Santa Cruz, CA 95064
3 Department of Neurobiology University of Pittsburgh, Pittsburgh, PA 15261

* To whom correspondence should be addressed.
Gregory J. Cole, E-mail: gcole{at}nccu.edu


  Abstract

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 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 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 co-localizes 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.

Keywords: agrin/{alpha}-synuclein/Parkinson’s disease/heparan sulfate proteoglycan/protein conformational disorders.
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[Abstract] [Full Text] [PDF]


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