I-HSUAN LIUUversky, V.N.V.N.UverskyMunishkina, L.A.L.A.MunishkinaFink, A.L.A.L.FinkHalfter, W.W.HalfterCole, G.J.G.J.Cole2018-09-102018-09-102005http://www.scopus.com/inward/record.url?eid=2-s2.0-28444458083&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/313703Recent 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 β-amyloid (Aβ) plaques in AD. We have extended the analysis of agrin's function in neurodegenerative diseases to investigate its role in Parkinson's disease (PD). α-Synuclein is a critical molecular determinant in familial and sporadic PD, with the formation of α-synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to α-synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by β-sheet structure, and enhances insolubility of α-synuclein. We also show that agrin accelerates the formation of protofibrils by α-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 α-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. © The Author 2005. Published by Oxford University Press. All rights reserved.[SDGs]SDG3journal article10.1093/glycob/cwj014